CGRP antagonists

ABSTRACT

The present invention relates to novel CGRP antagonists of the general formula (I) in which U, V, X, Y, R 1 , R 2 , R 3  are defined as described below, the tautomers, isomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof, and the hydrates of the salts, particularly the physiologically compatible salts thereof having inorganic or organic acids or bases, pharmaceuticals comprising said compounds, the use thereof, and the method for the production thereof.

The present invention relates to new CGRP-antagonists of general formulaI

wherein U, V, X, Y, R¹, R² and R³ are defined as stated hereinafter, thetautomers, the isomers, the diastereomers, the enantiomers, thehydrates, the mixtures thereof and the salts thereof and the hydrates ofthe salts, particularly the physiologically acceptable salts thereofwith inorganic or organic acids or bases, pharmaceutical compositionscontaining these compounds, their use and processes for preparing them.

DETAILED DESCRIPTION OF THE INVENTION

In the above general formula I in a first embodiment

-   R¹ denotes a group of general formula IIa or IIb

-    and-   R² denotes H or C₁₋₃-alkyl, or-   R¹ and R² together with the nitrogen atom to which they are bound    denote a group of general formulae IIIa or IIIb

-   G denotes C—R^(1.1) or N,-   T denotes N—R^(1.2) or O,-   R^(1.1) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —C(O)—O—C₁₋₃-alkyl, C₂₋₄-alkenyl, —C₂₋₄-alkynyl, C₁₋₃-alkyl-S,        cyclopropyl, —NH₂, —COOH, —NH—C(O)—O—C₁₋₃-alkyl,        —NH—C(O)—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl group or C₁₋₃-alkyl-O— group wherein each        methylene group is substituted by up to two fluorine atoms and        each methyl group is substituted by up to three fluorine atoms,-   R^(1.2) independently of one another denote    -   (a) H or    -   (b) C₁₋₃-alkyl,-   R^(1.3) denotes    -   (a) H,    -   (b) F, —CN, C₁₋₃-alkyl, —CO₂—R^(1.3.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group may be        substituted by up to two fluorine atoms and each methyl group        may be substituted by up to three fluorine atoms,-   R^(1.3.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl,-   R³ a 6 or 10-membered aryl group substituted by the groups R^(3.1),    R^(3.2) and R^(3.3) or    -   a 6-membered heteroaryl group substituted by the groups R^(3.1),        R^(3.2) and R^(3.3) which is attached via a carbon atom,-   R^(3.1) denotes    -   (a) H,    -   (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O₂)—NH, —CN, —OH,        —O—C(O)—NH—C₁₋₃-alkyl,    -   (c) C₁₋₄-alkyl, R^(3.1.1)—C₁₋₃-alkylene, C₂₋₄-alkenyl,        C₂₋₄-alkynyl, C₁₋₃-alkyl-O, C₁₋₃-alkyl-S(O)_(m), cyclopropyl,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (e) —C(O)—R^(3.1.2),    -   (f) —S(O)₂—R^(3.1.3),-   R^(3.1.1) denotes    -   (a) H,    -   (b) C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,    -   (c) (R^(3.1.1.1))₂N,    -   (d) a saturated, mono- or diunsaturated 5- or 6-membered        heterocyclic group which is substituted at a nitrogen atom by a        group R^(3.1.1.1) and is substituted at a carbon atom by one or        two groups R^(3.1.1.2), or    -   (e) a heteroaryl group which is substituted at a carbon atom by        a group R^(3.1.1.2),-   R^(3.1.1.1) independently of one another denote    -   (a) H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl,    -   (b) heterocyclyl,    -   (c) aryl-C₀₋₃-alkylene or heteroaryl-C₀₋₃-alkylene,-   R^(3.1.1.2) independently of one another denote    -   (a) H, F, C₁₋₃-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,        —CO(O)R^(3.1.1.2.1), H₂N, (C₁₋₄-alkyl)-NH, (C₁₋₄-alkyl)₂N,    -   (b) phenyl or phenyl-CH₂,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(3.1.1.2.1) denotes H, C₁₋₆-alkyl, benzyl,-   R^(3.1.2) denotes —O—C₁₋₃-alkyl, —OH, —NR^(3.1.2.1)R^(3.1.2.2),-   R^(3.1.2.1) denotes H, C₁₋₃-alkyl,-   R^(3.1.2.2) denotes H, C₁₋₃-alkyl,-   R^(3.1.2.1) and R^(3.1.2.2) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl,-   R^(3.1.3) denotes —O—C₁₋₃-alkyl, —NR^(3.1.3.1)R^(3.1.3.2),-   R^(3.1.3.1) denotes H, C₁₋₃-alkyl,-   R^(3.1.3.2) denotes H, C₁₋₃-alkyl,-   R^(3.1.3.1) and R^(3.1.3.2) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl,-   R^(3.2) denotes    -   (a) H,    -   (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O₂)—NH, —CN, —OH,        —O—C(O)—NH—C₁₋₃-alkyl,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S(O)_(m), cyclopropyl,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (e) —C(O)—R^(3.2.1),    -   (f) —S(O)₂—R^(3.2.2),-   R^(3.2.1) denotes —O—C₁₋₃-alkyl, —OH, —NR^(3.2.1.1)R^(3.2.1.2),-   R^(3.2.1.1) denotes H, C₁₋₃-alkyl,-   R^(3.1.1.2) denotes H, C₁₋₃-alkyl,-   R^(3.2.1.1) and R^(3.2.1.2) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl,-   R^(3.2.2) denotes —NR^(3.2.2.1)R^(3.2.2.2),-   R^(3.2.2.1) denotes H, C₁₋₃-alkyl,-   R^(3.2.2.2) denotes H, C₁₋₃-alkyl,-   R^(3.2.2.1) and R^(3.2.2.2) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl,-   R^(3.3) denotes    -   (a) H,    -   (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O₂)—NH, —CN, —OH,        —O—C(O)—NH—C₁₋₃-alkyl,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S(O)_(m), cyclopropyl,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (e) —C(O)—R^(3.3.1),    -   (f) —S(O)₂—R^(3.3.2),-   R^(3.3.1) denotes —O—C₁₋₃-alkyl, —OH, —NR^(3.3.1.1)R^(3.3.1.2),-   R^(3.3.1.1) denotes H, C₁₋₃-alkyl,-   R^(3.3.1.2) denotes H, C₁₋₃-alkyl,-   R^(3.3.1.1) and R^(3.3.1.2) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl,-   R^(3.3.2) denotes —O—C₁₋₃-alkyl, —NR^(3.3.2.1)R^(3.3.2.2),-   R^(3.3.2.1) denotes H, C₁₋₃-alkyl,-   R^(3.3.2.2) denotes H, C₁₋₃-alkyl,-   R^(3.3.2.1) and R^(3.3.2.2) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, or-   R^(3.2) und R^(3.3) together with the carbon atoms to which they are    attached form a monounsaturated 5-membered or a mono- or    diunsaturated 6-membered heterocyclic group or a 5- to 6-membered    heteroaryl group, wherein    -   the heterocycles mentioned previously may contain a carbonyl,        thiocarbonyl or cyanoimino group adjacent to a nitrogen atom,        and    -   may optionally be additionally substituted at one or two        nitrogen atoms by a group R^(3.3.3) in each case and    -   may optionally be additionally substituted at one or two carbon        atoms by one or two groups R^(3.3.4) in each case,-   R^(3.3.3) independently of one another denote    -   (a) C₁₋₄-alkyl or    -   (b) C₃₋₆-cycloalkyl,-   R^(3.3.4) independently of one another denote    -   (a) C₁₋₄-alkyl or    -   (b) C₃₋₆-cycloalkyl,    -   (c) halogen, CN, —O—C₁₋₃-alkyl, —NH₂,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   U denotes N,N-oxide or C—R⁴,-   V denotes N,N-oxide or C—R⁵,-   X denotes N,N-oxide or CR⁶,-   Y denotes N or C—R⁷,    -   while at most three of the previously mentioned groups U, V, X        or Y simultaneously denote a nitrogen atom,-   R⁴ denotes    -   (a) H,    -   (b) a C₁₋₆-alkyl or C₁₋₃-alkyl-O— group which is substituted in        each case by a group R^(4.1),    -   (c) R^(4.2)R^(4.3)N, R^(4.2)R^(4.3)N—C₁₋₃-alkylene,    -   (d) halogen, —CN, —OH, —COOH, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-O—C₁₋₃-alkylene, C₃₋₆-cycloalkyl,        C₃₋₆-cycloalkyl-C₁₋₄-alkylene, C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene,    -   (e) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.1) denotes H, OH or —O—CH₃,-   R^(4.2) denotes H or C₁₋₃-alkyl,-   R^(4.3) denotes H or C₁₋₃-alkyl, or-   R^(4.2) and R^(4.3) together with the nitrogen atom to which they    are bound denote a 3- to 6-membered heterocyclic group,-   R⁵ denotes    -   (a) H,    -   (b) a C₁₋₆-alkyl or C₁₋₃-alkyl-O— group which is substituted in        each case by a group R^(5.1),    -   (c) —NR^(5.2)R^(5.3), NR^(5.2)R^(5.3)—C₁₋₃-alkylene,    -   (d) halogen, —CN, —OH, C₁₋₃-alkyl-O—C₁₋₃-alkylene,        C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄-alkylene,        C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene,    -   (e) aryl-C₀₋₃-alkylen-O— group,    -   (f) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(5.1) denotes H, OH or —O—CH₃,-   R^(5.2) denotes H or C₁₋₆-alkyl,-   R^(5.3) denotes H, C₁₋₆-alkyl or —SO₂—C₁₋₃-alkyl, or-   R^(5.2) and R^(5.3) together with the nitrogen atom to which they    are bound denote a 3- to 6-membered heterocyclic group,-   R⁶ denotes    -   (a) H,    -   (b) a C₁₋₆-alkyl or C₁₋₃-alkyl-O— group which is substituted in        each case by a group R^(6.1),    -   (c) R^(6.2)R^(6.3)N, R^(6.2)R^(6.3)N—C₁₋₃-alkylene,    -   (d) halogen, —CN, —OH, —COOH, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-O—C₁₋₃-alkylene, C₃₋₆-cycloalkyl,        C₃₋₆-cycloalkyl-C₁₋₄-alkylene, C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene,    -   (e) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(6.1) denotes H, OH or —O—CH₃,-   R^(6.2) denotes H or C₁₋₃-alkyl,-   R^(6.3) denotes H or C₁₋₃-alkyl, or-   R^(6.2) and R^(6.3) together with the nitrogen atom to which they    are bound denote a 3- to 6-membered heterocyclic group, and-   R⁷ denotes H, halogen or C₁₋₃-alkyl,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof and the hydrates of the    salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A second embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y, R² and R³ are definedas hereinbefore in the first embodiment and

-   R¹ denotes a group selected from

-   R^(1.1) denotes    -   a) H,    -   b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —C(O)—O—C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-S,        —NH₂,    -   c) a C₁₋₃-alkyl group or C₁₋₃-alkyl-O— group wherein each        methylene group is substituted by up to two fluorine atoms and        each methyl group is substituted by up to three fluorine atoms,        and-   R^(1.2) denotes    -   (a) H or    -   (b) CH₃,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof and the hydrates of        the salts, particularly the physiologically acceptable salts        thereof with inorganic or organic acids or bases.

A third embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y and R³ are defined ashereinbefore in the first embodiment and

-   R¹ and R² together with the nitrogen atom to which they are bound    denote a group selected from

-   R^(1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —C(O)—O—C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-S,        —NH₂,    -   (c) a C₁₋₃-alkyl group or C₁₋₃-alkyl-O— group wherein each        methylene group is substituted by up to two fluorine atoms and        each methyl group is substituted by up to three fluorine atoms,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof and the hydrates of        the salts, particularly the physiologically acceptable salts        thereof with inorganic or organic acids or bases.

A fourth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y, R² and R³ are definedas hereinbefore in the first embodiment and

-   R¹ denotes a group selected from

-   R^(1.1) denotes    -   (a) F, CH₃, —OH, —O—CH₃ or    -   (b) CF₃,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof and the hydrates of        the salts, particularly the physiologically acceptable salts        thereof with inorganic or organic acids or bases.

A fifth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y and R³ are defined ashereinbefore in the first embodiment and

-   R¹ and R² together with the nitrogen atom to which they are bound    denote a group selected from

-   R^(1.1) denotes    -   (a) F, CH₃, —OH, —O—CH₃ or CF₃,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof and the hydrates of        the salts, particularly the physiologically acceptable salts        thereof with inorganic or organic acids or bases.

A sixth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y, R² and R³ are definedas hereinbefore in the first embodiment and

-   R¹ denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the salts,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases.

A seventh embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y and R³ are defined ashereinbefore in the first embodiment and

-   R¹ and R² together with the nitrogen atom to which they are bound    denote a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the salts,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases.

An eighth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y, R¹ and R² are definedas hereinbefore in the first, second, fourth or sixth embodiment and

-   R³ denotes a group of general formula IV

-   A independently of one another denote C—H, C—F or N,-   R^(3.1) denotes    -   (a) H,    -   (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O)₂—NH, —CN, —OH,        —O—C(O)—NH—C₁₋₃-alkyl,    -   (c) C₁₋₄-alkyl, R^(3.1.1)—C₁₋₃-alkylene, C₂₋₄-alkenyl,        C₂₋₄-alkynyl, C₁₋₃-alkyl-O, C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (e) —C(O)—R^(3.1.2),    -   (f) —S(O)₂—R^(3.1.3),-   R^(3.1.1) denotes    -   (a) H,    -   (b) C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,    -   (c) (R^(3.1.1.1))₂N,    -   (d) a saturated, mono- or diunsaturated 5- or 6-membered        heterocyclic group which is substituted at a nitrogen atom by a        group R^(3.1.1.1) and is substituted at a carbon atom by one or        two groups R^(3.1.1.2), or    -   (e) a heteroaryl group which is substituted at a carbon atom by        a group R^(3.1.1.2),-   R^(3.1.1.1) independently of one another denote    -   (a) H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl,    -   (b) heterocyclyl,    -   (c) aryl-C₀₋₃-alkylene or heteroaryl-C₀₋₃-alkylene,-   R^(3.1.1.2) independently of one another denote    -   (a) H, F, C₁₋₃-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,        —CO(O)R^(3.1.1.2.1), H₂N, (C₁₋₄-alkyl)-NH, (C₁₋₄-alkyl)₂N,    -   (b) phenyl or phenyl-CH₂,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(3.1.1.2.1) denotes H, C₁₋₆-alkyl, benzyl,-   R^(3.1.2) denotes —O—C₁₋₃-alkyl, —OH, —NR^(3.1.2.1)R^(3.1.1.2),-   R^(3.1.2.1) denotes H, C₁₋₃-alkyl,-   R^(3.1.2.2) denotes H, C₁₋₃-alkyl,-   R^(3.1.3) denotes —NR^(3.1.3.1)R^(3.1.3.2),-   R^(3.1.3.1) denotes H, C₁₋₃-alkyl,-   R^(3.1.3.2) denotes H, C₁₋₃-alkyl,-   R^(3.2) denotes    -   (a) H,    -   (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O)₂—NH, —CN, —OH,        —O—C(O)—NH—C₁₋₃-alkyl,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (e) —C(O)—R^(3.2.1),    -   (f) —S(O)₂—R^(3.2.2),-   R^(3.2.1) denotes —O—C₁₋₃-alkyl, —OH, —NR^(3.2.1.1)R^(3.2.1.2),-   R^(3.2.1.1) denotes H, C₁₋₃-alkyl,-   R^(3.2.1.2) denotes H, C₁₋₃-alkyl,-   R^(3.2.2) denotes —NR^(3.2.2.1)R^(3.2.2.2),-   R^(3.2.2.1) denotes H, C₁₋₃-alkyl,-   R^(3.2.2.2) denotes H, C₁₋₃-alkyl,-   R^(3.3) denotes    -   (a) H,    -   (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O)₂—NH, —CN, —OH,        —O—C(O)—NH—C₁₋₃-alkyl,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (e) —C(O)—R^(3.3.1),    -   (f) —S(O)₂—R^(3.3.2),-   R^(3.3.1) denotes —O—C₁₋₃-alkyl, —OH, —NR^(3.3.1.1)R^(3.3.1.2),-   R^(3.3.1.1) denotes H, C₁₋₃-alkyl,-   R^(3.3.1.2) denotes H, C₁₋₃-alkyl,-   R^(3.3.2) denotes —O—C₁₋₃-alkyl, —NR^(3.3.2.1)R^(3.3.2.2),-   R^(3.3.2.1) denotes H, C₁₋₃-alkyl,-   R^(3.3.2.2) denotes H, C₁₋₃-alkyl, or-   R^(3.2) and R^(3.3) together with the carbon atoms to which they are    attached form a monounsaturated 5-membered or a mono- or    diunsaturated 6-membered heterocyclic group or a 5- to 6-membered    heteroaryl group, wherein    -   the heterocycles mentioned previously may contain a carbonyl,        thiocarbonyl or cyanoimino group adjacent to a nitrogen atom,        and    -   may optionally be additionally substituted at one or two        nitrogen atoms by a group R^(3.3.3) in each case and    -   may optionally be additionally substituted at one or two carbon        atoms by one or two groups R^(3.3.4) in each case,-   R^(3.3.3) independently of one another denote    -   (a) C₁₋₄-alkyl or    -   (b) C₃₋₆-cycloalkyl,-   R^(3.3.4) independently of one another denote    -   (a) C₁₋₄-alkyl, C₃₋₆-cycloalkyl,    -   (b) halogen, CN, C₁₋₃-alkyl-O—, —NH₂,    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof and the hydrates of        the salts, particularly the physiologically acceptable salts        thereof with inorganic or organic acids or bases.

A ninth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y, R¹ and R² are definedas hereinbefore in the first, second, fourth or sixth embodiment and

-   R³ denotes a group of general formula IV

-   A independently of one another denote C—H, C—F or N,-   R^(3.1) denotes    -   (a) H,    -   (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, —CN, —OH, —O—C(O)—NH—C₁₋₃-alkyl,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.2) denotes    -   (a) H,    -   (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, —CN, —OH, —O—C(O)—NH—C₁₋₃-alkyl,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.3) denotes    -   (a) H,    -   (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, —CN, —OH, —O—C(O)—NH—C₁₋₃-alkyl,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.2) and R^(3.3) together with the carbon atoms to which they are    attached form a monounsaturated 5-membered or a mono- or    diunsaturated 6-membered heterocyclic group or a 5- to 6-membered    heteroaryl group, wherein    -   the heterocycles mentioned previously may contain a carbonyl,        thiocarbonyl or cyanoimino group adjacent to a nitrogen atom,        and    -   may optionally be additionally substituted at one or two        nitrogen atoms by a group R^(3.3.3) in each case and    -   may optionally be additionally substituted at one or two carbon        atoms by one or two groups R^(3.3.4) in each case,-   R^(3.3.3) independently of one another denote    -   (a) C₁₋₄-alkyl or    -   (b) C₃₋₆-cycloalkyl,-   R^(3.3.4) independently of one another denote    -   (a) C₁₋₄-alkyl, C₃₋₆-cycloalkyl,    -   (b) halogen, CN, C₁₋₃-alkyl-O—, —NH₂,    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof and the hydrates of        the salts, particularly the physiologically acceptable salts        thereof with inorganic or organic acids or bases.

A tenth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y, R¹ and R² are definedas hereinbefore in the first, second, fourth or sixth embodiment and

-   R³ denotes a group of general formula IVa

-   R^(3.1) denotes    -   (a) H,    -   (b) F, Cl, Br, —NH₂, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, —CN, —OH,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.2) denotes    -   (a) H,    -   (b) F, Cl, Br, H₂N, (C₁₋₄-alkyl)-NH, (C₁₋₄-alkyl)₂N,        (C₁₋₃-alkyl)-C(O)—NH, —OH,    -   (c) C₁₋₄-alkyl,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.3) denotes    -   (a) H,    -   (b) F, Cl, Br, H₂N, (C₁₋₄-alkyl)-NH, (C₁₋₄-alkyl)₂N,        (C₁₋₃-alkyl)-C(O)—NH, —OH,    -   (c) C₁₋₄-alkyl,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.2) and R^(3.3) together with the carbon atoms to which they are    attached form a monounsaturated 5-membered or a mono- or    diunsaturated 6-membered heterocyclic group or a 5- to 6-membered    heteroaryl group, wherein    -   the heterocycles mentioned previously may contain a carbonyl,        thiocarbonyl or cyanoimino group adjacent to a nitrogen atom,        and    -   may optionally be additionally substituted at one or two        nitrogen atoms by a group R^(3.3.3) in each case and    -   may optionally be additionally substituted at one or two carbon        atoms by one or two groups R^(3.3.4) in each case,-   R^(3.3.3) independently of one another denote    -   (a) C₁₋₄-alkyl or    -   (b) C₃₋₆-cycloalkyl,-   R^(3.3.4) independently of one another denote    -   (a) C₁₋₄-alkyl, C₃₋₆-cycloalkyl,    -   (b) halogen, CN, C₁₋₃-alkyl-O—, —NH₂,    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, and-   R^(3.4) denotes H or F,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof and the hydrates of the    salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

An eleventh embodiment of the present invention comprises the compoundsof the above general formula I, wherein U, V, X, Y, R¹ and R² aredefined as hereinbefore in the first, second, fourth or sixth embodimentand

-   R³ denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the salts,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases.

A twelfth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein U, V, X, Y, R¹ and R² are asdefined hereinbefore in the first, second, third, fourth, fifth, sixthor seventh embodiment and

-   R³ denotes a group of general formula IVb

-   R^(3.1) denotes    -   (a) H,    -   (b) F, Cl, Br, —NH₂, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, —CN, —OH,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.2) and R^(3.3) together with the carbon atoms to which they are    bound form a monounsaturated 5-membered heterocyclic group or a    mono- or diunsaturated 6-membered heterocyclic group or a 5- to    6-membered heteroaryl group, wherein    -   the previously mentioned heterocycles contain a carbonyl,        thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and    -   may each optionally additionally be substituted at one or two        nitrogen atoms by a group R^(3.3.3) and    -   may each optionally additionally be substituted at one or two        carbon atoms by one or two groups R^(3.3.4),-   R^(3.3.3) independently of one another denote    -   (a) C₁₋₄-alkyl or    -   (b) C₃₋₆-cycloalkyl, and-   R^(3.3.4) independently of one another denote    -   (a) C₁₋₄-alkyl, C₃₋₆-cycloalkyl,    -   (b) halogen, —CN, —O—C₁₋₃-alkyl, —NH₂,    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof and the hydrates of        the salts, particularly the physiologically acceptable salts        thereof with inorganic or organic acids or bases.

A thirteenth embodiment of the present invention comprises the compoundsof the above general formula I, wherein U, V, X, Y, R¹ and R² are asdefined hereinbefore in the first, second, third, fourth, fifth, sixthor seventh embodiment and

-   R³ denotes a group of general formula IVb

-   R^(3.1) denotes    -   (a) H,    -   (b) F, Cl, Br, —NH₂, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, —CN, —OH,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.2) and R^(3.3) together with the carbon atoms to which they are    bound form a monounsaturated 5-membered heterocyclic group or a    5-membered heteroaryl group, wherein    -   the previously mentioned heterocycles contain a carbonyl,        thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and    -   may each optionally additionally be substituted at one or two        nitrogen atoms by a group R^(3.3.3) and    -   may each optionally additionally be substituted at one or two        carbon atoms by one or two groups R^(3.3.4),-   R^(3.3.3) independently of one another denote    -   (a) C₁₋₄-alkyl or    -   (b) C₃₋₆-cycloalkyl, and-   R^(3.3.4) independently of one another denote    -   (a) C₁₋₄-alkyl, C₃₋₆-cycloalkyl,    -   (b) halogen, —CN, —O—C₁₋₃-alkyl, —NH₂,    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof and the hydrates of        the salts, particularly the physiologically acceptable salts        thereof with inorganic or organic acids or bases.

A fourteenth embodiment of the present invention comprises the compoundsof the above general formula I, wherein U, V, X, Y, R¹ and R² are asdefined hereinbefore in the first, second, third, fourth, fifth, sixthor seventh embodiment and

-   R³ denotes a group of general formula IVc

-   T denotes O, S, CH₂, NH or N—R^(3.3.3),-   R^(3.1) denotes    -   (a) H,    -   (b) F, Cl, Br, —NH₂, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂N,        C₁₋₃-alkyl-C(O)—NH, —CN, —OH,    -   (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-S,    -   (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, and-   R^(3.3.3) independently of one another denote    -   (a) C₁₋₄-alkyl or    -   (b) C₃₋₆-cycloalkyl,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof and the hydrates of        the salts, particularly the physiologically acceptable salts        thereof with inorganic or organic acids or bases.

A fifteenth embodiment of the present invention comprises the compoundsof the above general formula I, wherein U, V, X, Y, R¹ and R² are asdefined hereinbefore in the first, second, third, fourth, fifth, sixthor seventh embodiment and

-   R³ denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the salts,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases.

A sixteenth embodiment of the present invention comprises the compoundsof the above general formula I, wherein Y, R¹, R² and R³ are as definedhereinbefore in the first, second, third, fourth, fifth, sixth, seventh,eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth orfifteenth embodiment and

-   U—V—X denotes a group selected from-   —N═N—(C—R⁶)═, —N═(C—R⁵)—N═, —N═(C—R⁵)—(C—R⁶)═,    —(N-oxide)=(C—R⁵)—(CR⁶)═, —(CR⁴)═N—N═, —(CR⁴)═N—(CR⁶)═,    —(C—R⁴)═N(oxide)-(C—R⁶)═, —(CR⁴)═(C—R⁵)—N═,    —(CR⁴)═(C—R⁵)—(N-oxide)=, —(CR⁴)═(C—R⁵)—(CR⁶)═, and-   R⁴ denotes    -   (a) H,    -   (b) a C₁₋₆-alkyl or C₁₋₃-alkyl-O— group which is substituted in        each case by a group R^(4.1),    -   (c) R^(4.2)R^(4.3)N, R^(4.2)R^(4.3)N—C₁₋₃-alkylene,    -   (d) halogen, —CN, —OH, —COOH, C₁₋₃alkyl-O,        C₁₋₃-alkyl-O—C₁₋₃-alkylene, C₃₋₆-cycloalkyl,        C₃₋₆-cycloalkyl-C₁₋₄-alkylene, C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene,    -   (e) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.1) denotes H, OH or —O—CH₃,-   R^(4.2) denotes H or C₁₋₃-alkyl,-   R^(4.3) denotes H or C₁₋₃-alkyl, or-   R^(4.2) and R^(4.3) together with the nitrogen atom to which they    are bound denote a 3- to 6-membered heterocyclic group,-   R⁵ denotes    -   (a) H,    -   (b) a C₁₋₆-alkyl or C₁₋₃-alkyl-O— group which is substituted by        a group R^(5.1) in each case,    -   (c) —NR^(5.2)R^(5.3), NR^(5.2)R^(5.3)—C₁₋₃-alkylene,    -   (d) halogen, —CN, —OH, C₁₋₃-alkyl-O—C₁₋₃-alkylene,        C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄-alkylene,        C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene,    -   (e) aryl-C₀₋₃-alkylen-O— group,    -   (f) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(5.1) denotes H, OH or —O—CH₃,-   R^(5.2) denotes H or C₁₋₆-alkyl,-   R^(5.3) denotes H, C₁₋₆-alkyl or —SO₂—C₁₋₃-alkyl-   R⁶ denotes    -   (a) H,    -   (b) a C₁₋₆-alkyl or C₁₋₃-alkyl-O— group which is substituted in        each case by a group R^(6.1),    -   (c) R^(6.2)R^(6.3)N, R^(6.2)R^(6.3)N—C₁₋₃-alkylene,    -   (d) halogen, —CN, —OH, —COOH, C₁₋₃-alkyl-O,        C₁₋₃-alkyl-O—C₁₋₃-alkylene, C₃₋₆-cycloalkyl,        C₃₋₆-cycloalkyl-C₁₋₄-alkylene, C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene,    -   (e) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(6.1) denotes H, OH or —O—CH₃,-   R^(6.2) denotes H or C₁₋₃-alkyl,-   R^(6.3) denotes H or C₁₋₃-alkyl, or-   R^(6.2) and R^(6.3) together with the nitrogen atom to which they    are bound denote a 3- to 6-membered heterocyclic group,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof and the hydrates of the    salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A seventeenth embodiment of the present invention comprises thecompounds of the above general formula I, wherein Y, R¹, R² and R³ areas defined hereinbefore in the first, second, third, fourth, fifth,sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth,fourteenth or fifteenth embodiment and the ring

denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the salts,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases.

An eighteenth embodiment of the present invention comprises thecompounds of the above general formula I wherein

-   R¹ denotes a group selected from

-   R² denotes H,-   R³ denotes a group selected from

-   the ring

-    denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the salts,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases.

A nineteenth embodiment of the present invention comprises the compoundsof the above general formula I wherein

-   R¹ and R² together with the nitrogen atom to which they are bound    denote a group selected from

-   R³ denotes a group selected from

-   and the ring

-    denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the salts,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases.

The following compounds are mentioned as examples of most particularlypreferred compounds of the above general formula I:

No. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

the enantiomers, the diastereomers, the hydrates, the mixtures thereofand the salts thereof and the hydrates of the salts, particularly thephysiologically acceptable salts thereof with inorganic or organic acidsor bases.

Terms and Definitions Used

The present specification of the invention is to be interpreted inaccordance with the conventions and rules of chemical bonds.

The compounds included in this invention are those that are alsochemically stable.

Unless otherwise stated, all the substituents are independent of oneanother. If for example there are a plurality of C₁₋₄-alkyl groups assubstituents in one group, in the case of three C₁₋₄-alkyl substituents,independently of one another, one may represent methyl, one ethyl andone n-propyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. If present, an asterisk (*) in the structural formula of thesubstituent is to be understood as being the linking point to the restof the molecule. For example a phenyl group is shown as follows:

Moreover, the atom of the substituent that follows the linking point isunderstood as being the atom at position number 1.

The subject-matter of this invention also includes the compoundsaccording to the invention, including the salts thereof, wherein one ormore hydrogen atoms, for example one, two, three, four or five hydrogenatoms, are replaced by deuterium.

By the term “C₁₋₃-alkyl” (including those which are a part of othergroups) are meant branched and unbranched alkyl groups with 1 to 3carbon atoms, by the term “C₁₋₄-alkyl” are meant branched and unbranchedalkyl groups with 1 to 4 carbon atoms and by the term “C₁₋₆-alkyl” aremeant branched and unbranched alkyl groups with 1 to 6 carbon atoms.Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, pentyl, neopentyl or n-hexyl. Theabbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionallyalso be used for the above-mentioned groups. Unless stated otherwise,the definitions propyl and butyl include all the possible isomeric formsof the groups in question. Thus, for example, propyl includes n-propyland iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁₋₆-alkylene” (including those which are a part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₃-alkylene” are meant branched andunbranched alkylene groups with 1 to 3 carbon atoms. Examples include:methylene, ethylene, propylene, 1-methylethylene, butylene,1-methylpropylene, 1.1-dimethylethylene, 1,2-dimethylethylene,pentylene, 1.1-dimethylpropylene, 2,2-dimethylpropylene,1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless statedotherwise, the definition propylene includes all the possible isomericforms of the groups in question with the same number of carbons. Thus,for example, propyl also includes 1-methylethylene and butylene includes1-methylpropylene, 1.1-dimethylethylene, 1,2-dimethylethylene.

The definition for C₀-alkylene denotes a bond.

By the term “C₂₋₆-alkenyl” (including those which are a part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theycomprise at least one double bond. Alkenyl groups with 2 to 4 carbonatoms are preferred. Examples include: ethenyl or vinyl, propenyl,butenyl, pentenyl, or hexenyl. Unless stated otherwise, the definitionspropenyl, butenyl, pentenyl and hexenyl include all the possibleisomeric forms of the groups in question. Thus, for example, propenylincludes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkynyl” (including those which are a part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theycomprise at least one triple bond. Examples include: ethynyl, propynyl,butynyl, pentynyl, or hexynyl. Unless stated otherwise, the definitionspropynyl, butynyl, pentynyl and hexynyl include all the possibleisomeric forms of the groups in question. Thus for example propynylincludes 1-propynyl and 2-propynyl, butynyl includes 1,2- and 3-butynyl,1-methyl-1-propynyl, 1-methyl-2-propynyl etc.

By the term “C₃₋₆-cycloalkyl” (including those which are a part of othergroups) are meant cyclic alkyl groups with 3 to 6 carbon atoms and bythe term “C₅₋₆-cycloalkyl” are meant cyclic alkyl groups with 5 to 6carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Unless otherwise stated, the cyclic alkyl groups may besubstituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “C₅₋₆-cycloalkenyl” (including those which are a part ofother groups) are meant cyclic alkenyl groups with 5 or 6 carbon atoms,which contain an unsaturated bond. Examples include: cyclopentenyl orcyclohexenyl. Unless otherwise stated, the cyclic alkenyl groups may besubstituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “heterocyclyl” or “heterocyclic group” are meant, unlessotherwise described in the definitions, stable 5-, 6- or 7-memberedmonocyclic or 8-, 9-, 10- or 11-membered bicyclic heterocyclic ringsystems which do not form an aromatic ring system in at least one ringand besides carbon atoms may carry one to four heteroatoms, which areselected from among nitrogen, oxygen and sulphur. Both nitrogen atomsand sulphur atoms may optionally be oxidised and nitrogen atoms may bequaternised. The heterocyclic ring may contain one or two carbonyl,thiocarbonyl or cyanoimino groups adjacent to a nitrogen atom. Theheterocycles mentioned previously may be attached to the rest of themolecule via a carbon atom or a nitrogen atom.

Unless otherwise stated, the heterocycles may be substituted by one ormore groups selected from among:

-   -   (a) OH, NO₂, CN, OCF₃, OCHF₂, OCH₂F, NH₂,    -   (b) halogen, preferably fluorine or chlorine,    -   (c) C₁₋₆-alkyl, preferably C₁₋₃-alkyl, particularly preferably        ethyl, methyl, iso-propyl or tert-butyl,    -   (d) —SO₂—O—C₁₋₃-alkyl, preferably —O-methyl,    -   (e) —O—C₁₋₃-alkyl, preferably —O-methyl or —O-ethyl,    -   (f) COOH, COO—C₁₋₃-alkyl, preferably CO—O-methyl or CO—O-ethyl,        while the groups may be identical or different.

The following compounds are mentioned by way of example, but theinvention is not restricted to them: azetidine, oxetane, thietane,thietane dioxide, tetrahydrofuran, dihydrofuran, dioxolane,imidazolidine, imidazoline, imidazolidinone, dihydroimidazolone,oxazoline, oxazolidine, oxazolidinone, pyrrolidinone, dihydropyrazole,pyrrolidine, pyrroline, morpholine, tetrahydropyridine, dihydropyran,tetrahydropyran, dioxane, piperazine, piperidine, piperazinone,piperidinone, pyran, thiomorpholine-S-oxide, thiomorpholine-S-dioxide,thiomorpholine, dihydroxazine, morpholinedione, morpholinethione,perhydrothiazinedioxide, {acute over (ε)}-caprolactam, oxazepanone,diazepanone, thiazepanone, perhydroazepine, dihydroquinazolinone,dihydroindole, dihydroisoindole, benzoxazolone, benzimidazolone,chromanone, tetrahydroquinoline, tetrahydrobenzoxazole,tetrahydrobenzisoxazole, tetrahydrobenzthiophene,tetrahydrothieno-pyridine, tetrahydrobenzofuran,tetrahydro-oxazolopyridine, tetrahydro-isoxazolopyridine.

The following heterocycles are preferred according to the invention:

By the term “aryl” (including those which are a part of other groups)are meant monocyclic aromatic ring systems with 6 carbon atoms orbicyclic aromatic ring systems with 10 carbon atoms. Examples includephenyl, 1-naphthyl or 2-naphthyl; the preferred aryl group is phenyl.

Unless otherwise stated, the aromatic groups may be substituted by oneor more groups selected from among:

-   -   (a) OH, NO₂, CN, OCF₃, OCHF₂, OCH₂F, NH₂,    -   (b) halogen, preferably fluorine or chlorine,    -   (c) C₁₋₆-alkyl, preferably C₁₋₃-alkyl, particularly preferably        ethyl, methyl, iso-propyl or tert-butyl,    -   (d) —SO₂—O—C₁₋₃-alkyl, preferably —O-methyl,    -   (e) —O—C₁₋₃-alkyl, preferably —O-methyl or —O-ethyl,    -   (f) COOH, CO—O—C₁₋₃-alkyl, preferably CO—O-methyl or CO—O-ethyl,        while the groups may be identical or different.

By the term “heteroaryl” are meant stable five- or six-memberedheterocyclic aromatic groups or 8- to 10-membered bicyclic heteroarylrings that may contain in each ring one, two or three heteroatoms,selected from among oxygen, sulphur and nitrogen, and additionallysufficient conjugated double bonds to form an aromatic system. Examplesof five- or six-membered heterocyclic aromatic groups are as follows,but the invention is not restricted to these:

-   furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole,    isothiazole, isoxazole, oxadiazole, triazole, tetrazole, furazan,    thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine.

The following five-membered heterocyclic aromatic groups are preferredaccording to the invention:

The following six-membered heterocyclic aromatic groups are preferredaccording to the invention:

Examples of 9- or 10-membered bicyclic heteroaryl rings are as follows,but the invention is not restricted to these:

-   indole, isoindole, indazole, indolizine, benzofuran, benzthiophene,    benzimidazole, benzoxazole, benzothiazole, benzotriazole,    benzisoxazole, benzisothiazole, quinoline, isoquinoline, cinnolin,    phthalazine, quinoxaline, quinazoline, pyridopyrimidine,    pyridopyrazine, pyridopyridazine, pyrimidopyrimidine, pteridine,    purine, quinolizine, benzoxazolecarbonitrile, quinoline,    isoquinoline, quinolizine, pteridine, purine, quinolizine,    benzoxazole-carbonitrile.

The following bicyclic heteroaryl rings are preferred according to thisinvention:

Unless otherwise stated, the heteroaryls previously mentioned may besubstituted by one or more groups selected from among:

-   -   (a) OH, NO₂, CN, OCF₃, OCHF₂, OCH₂F, NH₂,    -   (b) halogen, preferably fluorine or chlorine,    -   (c) C₁₋₆-alkyl, preferably C₁₋₃-alkyl, particularly preferably        ethyl, methyl, iso-propyl or tert-butyl,    -   (d) —SO₂—O—C₁₋₃-alkyl, preferably —O-methyl,    -   (e) —O—C₁₋₃-alkyl, preferably —O-methyl or —O-ethyl,    -   (f) COOH, CO—O—C₁₋₃-alkyl, preferably CO—O-methyl or CO—O-ethyl,        while the groups may be identical or different.

Bicyclic heteroaryl rings may preferably be substituted in the phenylgroup.

By the term “halogen” are meant fluorine, chlorine, bromine or iodineatoms.

Compounds of general formula I may have acid groups, mainly carboxylgroups, and/or basic groups such as e.g. amino functions. Compounds ofgeneral formula I may therefore be present as internal salts, as saltswith pharmaceutically useable inorganic acids such as for examplehydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid,sulphuric acid, methanesulphonic acid, ethanesulphonic acid,benzenesulphonic acid, p-toluenesulphonic acid or organic acids such asfor example malic acid, succinic acid, acetic acid, fumaric acid, maleicacid, mandelic acid, lactic acid, tartaric acid, citric acid or as saltswith pharmaceutically useable bases such as alkali or alkaline earthmetal hydroxides, e.g. sodium hydroxide or potassium hydroxide, orcarbonates, ammonia, zinc or ammonium hydroxides or organic amines suchas e.g. diethylamine, triethylamine, ethanolamine, diethanolamine,triethanolamine, cyclohexylamine, dicyclohexylamine, inter alia.

The compounds according to the invention may be present as racemates,provided that they have only one chiral element, but may also beobtained as pure enantiomers, i.e. in the (R) or (S) form.

Compounds with a carbon double bond may be present in both the E and Zform.

The following nitrogen-containing heteroaryls may be present indifferent tautomeric forms:

This means that the compound prepared in each case is not restricted toone tautomeric form but encompasses all tautomeric forms.

However, the application also includes the individual diastereomericpairs of antipodes or mixtures thereof, which are obtained if there ismore than one chiral element in the compounds of general formula I, aswell as the individual optically active enantiomers of which theabove-mentioned racemates are made up.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids.

So-called prodrugs of compounds of general formula I are alsoencompassed by this invention. The term prodrug is used to denote anymolecule that releases the active principle of general formula I in-vivoafter administration to mammals. The prodrug may have little or nopharmacological activity per se, but releases the active principle ofgeneral formula I in-vivo after administration and this has the activitydescribed. Prodrugs for compounds of general formula I may be preparedby modifying suitable functional groups in the compound of generalformula I, as known to the skilled man in this field. (H. Bundgaard(Editor), Design of Prodrugs. (1986), Elsevier)

This invention also includes those metabolites that are derived from thecompounds of general formula I. By metabolites are meant, in thiscontext, compounds that are formed in-vivo from the compound of generalformula I after administration. Examples of metabolites include:

-   -   methyl groups of the compound of general formula I may be        converted into the corresponding hydroxymethyl groups.        (—CH₃->—CH₂OH)    -   alkoxy groups of the compound of general formula I may be        converted into the corresponding hydroxyl groups. (—OR->—OH)    -   secondary amines of the compound of general formula I may be        converted into the corresponding primary amines. (—NR₁R₂->—NHR₁        or —NHR₂)    -   nitrogen atoms of the compound of general formula I may be        converted into the corresponding nitrogen oxides.        (═N—->═N⁺—(O⁻)—)

Methods of Preparation

The invention also relates to a process for preparing the compounds ofgeneral formula I, wherein the substituents have the meanings statedearlier.

Some methods of preparing the compounds of general formula I accordingto the invention

wherein U, V, X, Y, R¹, R² and R³ are as hereinbefore defined, areillustrated in the following synthesis schemes and Examples.

In some cases the order of carrying out the reaction schemes may bevaried in order to simplify the reactions or prevent unwantedby-products. The Examples that follow are provided to make the inventioncomprehensible. The Examples are intended to illustrate the inventionand should in no way restrict it.

In some cases the end product may be further derivatised, e.g. bymanipulation of the substituents. These manipulations may be generallyknown to the skilled man, such as oxidation, reduction, alkylation,acylation and hydrolysis, but need not be restricted to the above.

Starting compounds are prepared by processes which are either known inthe art or described herein. Before the reaction is carried outcorresponding functional groups in the compounds may be protected byconventional protective groups. These protective groups may be cleavedagain at a suitable stage within the reaction sequence using methodsknown in the art (P. G. M. Wuts, T. W. Greene “Greene's ProtectiveGroups in Organic Synthesis”, 4th ed., Wiley Interscience).

The compounds according to the invention may be prepared according tothe schemes and specific examples provided or correspondingmodifications, using known and/or available starting materials, reagentsand conventional methods of synthesis. Modifications to these reactionswhich are known to the skilled man but not described in detail here mayalso be implemented.

The following methods of preparing the compounds of general formula Iaccording to the invention and their precursors have proved particularlysuitable:

The starting compounds are commercially available or are prepared bymethods described in the literature, known to the skilled man in thefield or described herein. Before the reaction is carried out anycorresponding functional groups in the compounds may be protected byconventional protective groups. These protective groups may be cleavedagain at a suitable stage within the reaction sequence using methodsknown in the art.

In the reactions described below, any reactive groups present such ashydroxy, carboxy, amino, alkylamino, amide or imino groups may beprotected during the reaction by conventional protective groups that arecleaved again after the reaction.

For example

-   -   a suitable protective group for a hydroxy group may be the        methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl,        tert.-butyl, trityl, benzyl or tetrahydropyranyl group,    -   suitable protective groups for a carboxyl group may be the        trimethylsilyl, methyl, ethyl, tert.-butyl, benzyl or        tetrahydropyranyl group, and    -   suitable protective groups for an amide group may be the        N-methoxymethyl- (MOM), N-benzyloxymethyl (BOM),        N-(trimethylsilyl)ethoxymethyl (SEM),        N-tert-butyldimethylsiloxymethyl, N-tert-butyldimethylsilyl        (TBDMS), N-triisopropylsilyl- (TIPS), N-benzyl,        N-4-methoxybenzyl (PMB), N-triphenylmethyl (Trt),        N-tert-butoxycarbonyl (BOC), N-benzyloxycarbonyl (Cbz) or        N-trimethylsilylethylsulphonyl (SES)    -   a suitable protective group for an amino, alkylamino or imino        group may be the acetyl, trifluoroacetyl, benzoyl,        ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl,        methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for        the amino group, the phthalyl group.

Other protective groups and their cleavage are described in T. W.Greene, P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Wiley,2006.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide, or by ether splitting, e.g. in thepresence of iodotrimethylsilane, at temperatures between 0 and 100° C.,preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0 and 50° C., but preferablyat ambient temperature, and at a hydrogen pressure of 1 to 7 bar, butpreferably 1 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesof between 0 and 50° C., but preferably at ambient temperature.

A methoxy group is conveniently cleaved in the presence of borontribromide in a solvent such as methylene chloride at temperaturesbetween −35 and −25° C.

A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroaceticacid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxan or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxanat temperatures between 20 and 50° C.

A methoxymethyl group may be cleaved in the presence of an acid such asconcentrated hydrochloric acid in a solvent such as dimethoxyethane.Alternatively an acid such as trifluoroacetic acid may also be usedwithout a solvent.

An N-(trimethylsilyl)ethoxymethyl group may be cleaved in the presenceof TBAF and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone.Alternatively the SEM protective group may also be cleaved with an acidsuch as hydrogen chloride in an organic solvent such as dioxane orethanol.

An allyloxycarbonyl group is cleaved by treating with a catalytic amountof tetrakis-(triphenylphosphine)-palladium(0), preferably in a solventsuch as tetrahydrofuran and preferably in the presence of an excess of abase such as morpholine at temperatures between 0 and 100° C.,preferably at ambient temperature and under an inert gas, or by treatingwith a catalytic amount of tris-(triphenylphosphine)-rhodium(I)chloridein a solvent such as aqueous ethanol and optionally in the presence of abase such as 1,4-diazabicyclo[2,2,2]octane at temperatures between 20and 70° C.

The following methods of preparing the compounds of general formula Iaccording to the invention and their precursors have proved particularlysuitable:

An end compound of general formula I wherein U, V, X, Y, R¹, R² and R³are as hereinbefore defined may be obtained by reacting a compound ofgeneral formula (1-1) with an electron-poor compound of general formula(1-2) that has a leaving group LG. Halides, preferably chlorides andbromides, —SO₂CH₃, —OSO₂CH₃, —OSO₂C₆H₄—CH₃ or —S—CH₃ (—S—CH₃ requiresfurther reaction with an organic peroxide in order to be converted intothe actual leaving group) etc. may act as the leaving group LG, but itis not restricted to this list. The use of chlorides is mostparticularly preferred.

The reaction may be carried out by nucleophilic aromatic substitution inan inert solvent using an auxiliary base in a temperature range of from0° C. to the reflux temperature of the solvent. The reaction is carriedout in a suitable inert solvent, such as tetrahydrofuran, toluene,xylene, dialkylformamide (particularly preferably dimethylformamide),cyclic amide (particularly preferably N-methyl-pyrrolidone),1,4-dioxane, acetonitrile or in inert solvent mixtures. Suitableauxiliary bases include tertiary amines such as triethylamine orethyldiisopropylamine, alkali metal carbonates such as potassiumcarbonate or sodium carbonate, sodium hydride (NaH) or lithiumdiisopropylamide (LDA). The inert solvent used must be compatible withthe base used. The reaction is preferably carried out indimethylformamide, at temperatures between ambient temperature and thereflux temperature of the solvent, in the presence of a tertiary aminebase.

Alternatively the structures of general formula (1-3) shown in Scheme 1wherein U, V, X, Y, R¹, R² and R³ are as hereinbefore defined may besynthesised by transition metal-catalysed reactions. A compound ofgeneral formula (1-1) may react with a compound of general formula (1-2)that has a leaving group LG in an inert solvent in the presence of acatalyst and an auxiliary base. In addition, a suitable ligand may beused for the catalyst. Chlorides, bromides, iodides, trifluoroacetates,trifluoromethanesulphonates, methanesulphonates and toluenesulphonates,but this list is not restrictive. Xylene, tetrahydrofuran,dimethylformamide, dimethoxyethane, toluene, benzene, 1,4-dioxane,acetonitrile or solvent mixtures may be used as inert solvents. Thepreferred solvent is xylene. Suitable bases are particularly amine basessuch as e.g. triethylamine or diisopropylethylamine or also inorganicbases such as caesium carbonate, caesium acetate, potassium carbonate,sodium carbonate or potassium phosphate. Preferred reaction temperaturesare from RT to the reflux temperature of the solvent at normal pressure.Typical catalysts are e.g. transition metal catalysts, such as e.g.palladium catalysts of the tris(dibenzylideneacetone)-dipalladium(0),tetrakis-(triphenylphosphine)-palladium(0), palladium-(II)-acetate,Pd(PPh₃)₂Cl₂, Pd(CH₃CN)₂Cl₂, Pd(dppf)Cl₂ or palladium(II)-chloride type.Typical ligands are e.g. triphenylphosphine, triphenylarsene, BINAP,XPhos, XantPhos, or 2-(di-tert-butylphosphino)biphenyl.

Compounds of general formula (2-4), wherein U, V, X, Y, R¹, R² and R³are as hereinbefore defined, may be prepared as shown in Scheme 2.

The reaction starts from a compound of general formula (2-1) wherein Haldenotes a halogen atom, preferably chlorine, bromine or iodine. TheGrignard or lithiated compound of general formula (2-2) may be preparedfrom the correspondingly halogenated compound of general formula (2-1)either by a so-called halogen-metal exchange or by inserting the metalin a halogen-carbon bond. In order to synthesise the correspondinglithiated compound of general formula (2-2) the halogen-metal exchangemay be carried out for example with an organo-lithium compound such ase.g. n-, sec- or tert.-butyllithium. The corresponding magnesiumcompounds (Grignard compounds) may also be obtained by a halogen-metalexchange with a corresponding Grignard reagent such as e.g. isopropyl-or sec-butyl-magnesium bromide or isopropyl- or sec-butyl-magnesiumchloride or diisopropyl- or di-sec-butylmagnesium with or in thepresence of a salt such as e.g. lithium chloride that may accelerate themetallisation process. The corresponding transmetallisingorgano-magnesium compound may also be synthesised in-situ fromcorresponding precursors (cf. e.g. Angew. Chem. 2004, 116, 3396-3399 andAngew. Chem. 2006, 118, 165-169 and references contained therein). Inaddition, -ate complexes of the organo-magnesium compounds may also beused, resulting from the combination of e.g. butylmagnesium chloride orbromide or isopropyl-magnesium chloride or bromide and butyllithium.(cf. Angew. Chem. 2000, 112, 2594-2596 and Tetrahedron Lett. 2001, 42,4841-4844 and references contained therein). The halogen-metal exchangeis preferably carried out between −100° C. and 40° C., most particularlypreferred is a temperature range of from −80° C. to 10° C. in an inertsolvent, preferably alkylether (most particularly preferably diethylether), cyclic ether (most particularly preferably 1,4-dioxane ortetrahydrofuran), toluene, hexane or solvent mixtures thereof. Themagnesium or organolithium compounds thus obtained may optionally betransmetallised with metal salts such as e.g. cerium trichloride, zincchloride or zinc bromide, indium chloride or indium bromide, in order tosynthesise alternative organometallic compounds of general formula (2-2)that are also suitable for the reaction described. Alternatively theorgano-metallic compound (2-2) may also be prepared by inserting a metalinto a carbon-halogen bond. Lithium or magnesium are suitable elementalmetals for this transformation. The insertion reaction is preferablycarried out between −80° C. and 100° C., while most particularlypreferred is a temperature range from −70° C. to 40° C. in an inertsolvent, preferably alkylether (most particularly preferably diethylether), cyclic ether (most particularly preferably 1,4-dioxane ortetrahydrofuran), toluene, hexane or solvent mixtures thereof. In caseswhere no spontaneous reaction takes place it may be necessary toactivate the metal with e.g. 1,2-dibromoethane, iodine, trimethylsilylchloride, acetic acid, hydrogen chloride or ultrasound. The reaction ofthe organo-metallic compound of general formula (2-2) with a compound(2-3) is preferably carried out in a temperature range from −100° C. to100° C., while a temperature range from −80° C. to 50° C. isparticularly preferred. The reaction is carried out in an inert solvent,such as e.g. preferably alkylether (most particularly preferably diethylether, dimethoxyethan), cyclic ether (most particularly preferably1,4-dioxane or tetrahydrofuran), aromatic hydrocarbons (mostparticularly preferably toluene or benzene), hexane or solvent mixturesthereof. All the reactions may be carried out in the air, but it ispreferable to carry them out in a protective gas atmosphere such asargon or nitrogen. It may prove advantageous to temporarily protect thefunctional group in compound (2-3).

The lithium-substituted or magnesium-substituted compound of generalformula (2-2) may react in a desired manner with a compound of generalformula (2-3) that contains a carboxyl group or derivatives thereof suchas esters, nitriles, carboxylic acid chlorides or amides, such as e.g.grapevine amides. These reactions may often be carried out without anyadditional transition metal catalyst or transmetallisation to anothermetal such as e.g. cerium, indium or zinc. In some cases, however, thetwo modifications mentioned may also prove advantageous. Aromatic boricacids, esters derived therefrom, dialkylarylboranes oraryltrifluoroborates may be reacted with acid chlorides or carboxylicacids in the presence of a transition metal, such as e.g. palladium, ascatalyst, to obtain the corresponding ketones (V. Polackova, St. Tama,I. Augustinova, Iveta; Tetrahedron; 2006; 62; 50; 11675-11678 andreferences cited therein and R. Kakino, H. Narahashi, I. Shimizu, A.Yamamoto, Bull. Chem. Soc. Jpn., 2002, 75, 1333-1345).

The corresponding boron-substituted compound, such as e.g. boric acids,dialkylarylboranes or boric acid ester can be synthesised from themetallised species by reaction with a boron electrophil such as e.g. aboric acid ester or derivatives thereof. Boron-substituted compounds mayalso be synthesised from the halogenated or pseudohalogenated precursormolecules using a transition metal catalyst, preferably palladium, and aboron or borolan compound. (Tetrahedron Lett. 2003, 4895-4898 andreferences cited therein).

The metallisation and/or coupling reaction may also be carried out inmicroreactors and/or in the micromixer. The addition reactions may becarried out without any further additions or, in the case of unreactivereactants, promoters such as e.g. BF₃*OEt₂ may also be added (cf. M.Schlosser, Organometallics in Synthesis, John Wiley & Sons,Chichester/New York/Brisbane/Toronto/Singapore, 1994).

The halogenated compounds of general formula (2-1) are eithercommercially available or may be synthesised by methods known in thefield of organic chemistry or described in the specialist literature(cf. e.g. J. March, Advanced Organic Reactions, Reactions Mechanism, andStructure, 4th Edition, John Wiley & Sons, Chichester/NewYork/Brisbane/Toronto/Singapore, 1992 and literature cited therein). Theuse of transition metals and organometallic compounds for the synthesisis described in detail in monographs (cf. e.g. L. Brandsma, S. F.Vasilevsky, H. D. Verkruijsse, Application of Transition MetalsCatalysts in Organic Synthesis, Springer-Verlag, Berlin/Heidelberg,1999; M. Schlosser, Organometallics in Synthesis, John Wiley & Sons,Chichester/New York/Brisbane/Toronto/Singapore, 1994, P. J. Stang, F.Diederich, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH,Weinheim, 1997 and references contained therein.)

A method of synthesising compounds of general formula (3-4) wherein U,V, X, Y and R³ are as hereinbefore defined is illustrated in Scheme 3.

Starting from a halogenated compound (particularly preferred are thechlorides, bromides and iodides) of general formula (3-1) thecorresponding lithium or magnesium-substituted compound may besynthesised by a halogen-metal exchange reaction, e.g. withbutyllithium, isopropylmagnesium halide or diisopropylmagnesium or byinsertion of an elemental metal into the halogen-carbon bond. Thecorresponding boron-substituted compounds, such as e.g. boric acid,dialkylarylborane or boric acid ester, can be synthesised from themetallised species by reaction with a boron electrophil such as e.g. aboric acid ester or derivatives thereof. Boron-substituted compounds mayalso be synthesised from the halogenated or pseudohalogenated precursormolecules using a transition metal catalyst, preferably palladium, and aboron or borolan compound (Tetrahedron Lett. 2003, 4895-4898 andreferences cited therein). The lithium-substituted ormagnesium-substituted compound of general formula (3-2) may be added toa compound of general formula (3-3) that contains a carboxyl group orderivatives thereof such as esters, nitriles, carboxylic acid chloridesor amides, such as e.g. grapevine amides. These reactions may often becarried out without any additional transition metal catalyst ortransmetallisation to another metal such as e.g. cerium, indium or zinc.In some cases, however, the two modifications mentioned may also proveadvantageous. Aromatic boric acids, esters derived therefrom,dialkylarylboranes or aryltrifluoroborates may be reacted with acidchlorides or carboxylic acids in the presence of a transition metal,such as e.g. palladium, as catalyst, to obtain the corresponding ketones(V. Polackova, St. Toma, I. Augustinova, Iveta; Tetrahedron; 2006; 62;50; 11675-11678 and references cited therein and R. Kakino, H.Narahashi, I. Shimizu, A. Yamamoto, Bull. Chem. Soc. Jpn., 2002, 75,1333-1345).

Compounds of general formula (4-3), wherein U, V, X, Y and R³ are ashereinbefore defined, may be prepared as shown in Scheme 4.

A compound of general formula (4-1) that has a leaving group LG and anacid halide group may be reacted with an aromatic compound of generalformula (4-2) under Friedel-Crafts acylation conditions or variationsthereof. Friedel-Crafts reactions are carried out in the presence of acatalyst which is used in either catalytic or stoichiometric amounts.Suitable catalysts are, in particular, AlCl₃, FeCl₃, iodine, iron,ZnCl₂, sulphuric acid or trifluoromethanesuiphonic acid. Instead of theacid halide the corresponding carboxylic acid, anhydride, ester ornitrile may also be used. The reaction is preferably carried out inhalogenated hydrocarbons. Dichloromethane and 1,2-dichloroethane areparticularly preferred. Friedel-Crafts reactions are carried out in atemperature range of from −30° C. to 120° C., preferably from 30° C. to100° C. However, the reactions may also be carried out without asolvent. The reactions may also be carried out in the microwave.

Compounds of general formula (5-3), wherein U, V, X, Y, R¹, R² and R³are as hereinbefore defined, may be prepared as shown in Scheme 5.

Analogously to a method of T. Ishiyama et al. (J. Org. Chem., 1998, 63,4726) a compound of general formula (5-1) that has a leaving group LGmay be reacted with a boron-substituted compound, such as boric acid(R═H), boric acid ester (R=alkyl) dialkylarylborane in the presence of acatalyst and a base, in an inert solvent and a carbon monoxideatmosphere, preferably in a temperature range from ambient temperatureto the reflux temperature of the solvent. Preferably, elevated reactiontemperatures from 80° C. to 110° C. are used, under elevated carbonmonoxide pressure. A suitable ligand may additionally be used for thecatalyst. Alkali metal iodides such as sodium iodide or potassium iodidemay be added as additives. Bromides, iodides, trifluoroacetates,trifluoromethanesulphonates, methanesuiphonates and toluenesulphonatesmay act as the leaving group LG, although this list is not restrictive.The inert solvents used may be xylene, tetrahydrofuran,dimethylformamide, dimethoxyethane, toluene, benzene, anisole,1,4-dioxane, acetonitrile or solvent mixtures. The preferred solvent isanisol. Suitable bases are inorganic bases such as caesium carbonate,caesium acetate, potassium carbonate, sodium carbonate or potassiumphosphate. The reactions are carried out in a carbon monoxideatmosphere, in which the carbon monoxide pressure may be 1 to 50 bar.Typical catalysts are e.g. palladium catalysts such astris-(dibenzylideneacetone)-dipalladium(0),tetrakis-(triphenylphosphine)-palladium(0), palladium-(II)-acetate,Pd(PPh₃)₂Cl₂, Pd(CH₃CN)₂Cl₂, Pd(dppf)Cl₂ or palladium(II)-chloride.Typical ligands are e.g. triphenylphosphine, tricyclohexylphosphine,tri-tert-butylphosphine, triphenylarsene,2,2′-bis(diphenylphosphino)-1,1-binaphthyl (BINAP),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos),4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (XantPhos), or2-(di-tert-butylphosphino)biphenyl, 1,1′-bis(diphenylphosphino)ferrocene(Dppf), 1,2-bis(diphenylphosphino)ethane (dppe),1,3-bis(diphenylphosphino)propane(dppp) and1,4-bis(diphenylphosphino)butane (dppb).

It is particularly preferable to use Pd(PPh₃)₂Cl₂ as catalyst, potassiumcarbonate as base, 1 bar of carbon monoxide, potassium iodide asadditive and anisole as solvent. The corresponding boron-substitutedcompounds are either commercially obtainable or can be synthesised frommetallised compounds by reaction with a boron electrophil such as e.g. aboric acid ester or a derivative thereof. Moreover, theboron-substituted compounds may be prepared from the correspondinghalogenated or pseudohalogenated precursor molecules in a transitionmetal-catalysed reaction, e.g. with palladium and a diborolane orborolane compound. (Tetrahedron Lett. 2003, 4895-4898 and referencescited therein).

A method of synthesising compounds of general formula (6-3), wherein U,V, X, Y and R³ are as hereinbefore defined, is shown in Scheme 6:

Analogously to a method of A. Miyashita et al. (Heterocycles, 1997, Vol.45, No. 11, 2159-2173) compounds of general formula (6-1) that have aleaving group LG can be reacted with aromatic aldehydes in the presenceof a catalyst and a base in inert solvents to obtain compounds ofgeneral formula (6-3). Fluorides, chlorides, bromides, iodides,trifluoromethanesulphonates, methanesulphonates and toluenesulphonatesmay act as the leaving group LG, but the list is not restrictive.Particularly preferred are chlorides and bromides. Cyclic ethers(preferably tetrahydrofuran) and dialkylformamides (preferablydimethylformamide), may be used as inert solvents. Suitable catalystsare azolium salts, such as 1,3-dimethylimidazolium iodide or1,3-dimethylbenz-imidazolium iodide. Suitable bases are metal hydrides.Sodium hydride is most particularly preferred. The reactions are carriedout in a temperature range from RT to the reflux temperature of thesolvent. Elevated temperatures are preferred. The reaction may also becarried out with sodium p-tolylsulphinate instead of azolium salts andbase, in the presence of an alkali metal cyanide (preferably potassiumcyanide) in an inert solvent at elevated temperatures. (A. Miyashita etal., Heterocycles, 1998, Vol. 47, No. 1, 407-414).

Compounds of general formula (7-4) wherein U, V, X, Y and R³ are ashereinbefore defined, as shown in Scheme 7, may be prepared analogouslyto A. Miyashita et al., (Heterocycles, 1997, Vol. 45, No. 11, 2159-2173)and the literature cited therein.

Compounds of general formula (7-1) that have a leaving group LG may bereacted with 2-arylacetonitrile or 2-heteroarylacetonitrile in thepresence of a base in an inert solvent to obtain compounds of generalformula (7-3). Fluorides, chlorides, bromides, iodides,trifluoromethanesulphonates, methanesuiphonates and toluenesulphonatesmay act as the leaving group LG, but the list is not restrictive.Particularly preferred are chlorides and bromides. The inert solvent maybe a dialkylformamide (preferably dimethylformamide). Metal hydrides aresuitable as the base. Sodium hydride is most particularly preferred. Thereactions are carried out in a temperature range from RT to the refluxtemperature of the solvent. Preferably the reactions are carried out atelevated temperatures.

The compounds of general formula (7-4) are synthesised by oxidativedecyanisation of compounds of general formula (7-3). Oxidativedecyanisations are carried out in inert solvents through which oxygengas is passed in the presence of a base. Cyclic ethers (preferablytetrahydrofuran) may be used as inert solvents. Suitable bases are metalhydrides. Sodium hydride is most particularly preferred. The reactionsare carried out in a temperature range from −20° C. to the refluxtemperature of the solvent. Reactions are preferably carried out at RT.

The new compounds of general formula I according to the invention maycontain one or more chiral centres. If for example there are two chiralcentres present, the compounds may occur in the form of twodiastereomeric pairs of antipodes. The invention includes the individualisomers as well as the mixtures thereof. The diastereomers may beseparated on the basis of their different physico-chemical properties,e.g. by fractional crystallisation from suitable solvents, by highpressure liquid or column chromatography, using chiral or preferablynon-chiral stationary phases.

Racemates covered by general formula I may be separated for example byHPLC on suitable chiral stationary phases (e.g. chiral AGP, ChiralpakAD). Racemates which contain a basic or acidic function can also beseparated via the diastereomeric, optically active salts which areproduced on reacting with an optically active acid, for example (+) or(−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or(−)-monomethyl tartrate or (+) or (−)-camphorsulphonic acid, or anoptically active base, for example with (R)-(+)-1-phenylethylamine,(S)-(−)-1-phenylethylamine or (S)-brucine.

According to a conventional method of separating isomers, the racemateof a compound of general formula I is reacted with one of theabovementioned optically active acids or bases in equimolar amounts in asolvent and the resulting crystalline, diastereomeric, optically activesalts thereof are separated using their different solubilities. Thisreaction may be carried out in any type of solvent provided that it issufficiently different in terms of the solubility of the salts.Preferably, methanol, ethanol or mixtures thereof, for example in aratio by volume of 50:50, are used. Then each of the optically activesalts is dissolved in water, carefully neutralised with a base such assodium carbonate or potassium carbonate, or with a suitable acid, e.g.with dilute hydrochloric acid or aqueous methanesulphonic acid, and inthis way the corresponding free compound is obtained in the (+) or (−)form.

The (R) or (S) enantiomer alone or a mixture of two optically activediastereomeric compounds covered by general formula I may also beobtained by performing the syntheses described above with a suitablereaction component in the (R) or (S) configuration.

The new compounds of general formula I and the physiologicallyacceptable salts thereof have valuable pharmacological properties, basedon their selective CGRP-antagonistic properties. The invention furtherrelates to pharmaceutical compositions containing these compounds, theiruse and the preparation thereof.

The new compounds mentioned above and the physiologically acceptablesalts thereof have CGRP-antagonistic properties and exhibit goodaffinities in CGRP receptor binding studies. The compounds displayCGRP-antagonistic properties in the pharmacological test systemsdescribed hereinafter.

The following experiments were carried out to demonstrate the affinityof the above-mentioned compounds for human CGRP-receptors and theirantagonistic properties:

A. Binding Studies with SK-N-MC Cells (Expressing the Human CGRPReceptor)

SK-N-MC cells are cultivated in “Dulbecco's modified Eagle medium”. Themedium is removed from confluent cultures. The cells are washed twicewith PBS buffer (Gibco 041-04190 M), detached by the addition of PBSbuffer mixed with 0.02% EDTA, and isolated by centrifuging. Afterresuspension in 20 ml of “Balanced Salts Solution” [BSS (in mM): NaCl120, KCl 5.4, NaHCO₃ 16.2, MgSO₄ 0.8, NaHPO₄ 1.0, CaCl₂ 1.8, D-glucose5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100×g andresuspended in BSS. After the number of cells has been determined, thecells are homogenised using an Ultra-Turrax and centrifuged for 10minutes at 3000×g. The supernatant is discarded and the pellet isrecentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl₂, 1 mMEDTA, pH 7.40) enriched with 1% bovine serum albumin and 0.1%bacitracin, and resuspended (1 ml/1000000 cells). The homogenisedproduct is frozen at −80° C. The membrane preparations are stable formore than 6 weeks under these conditions.

After thawing, the homogenised product is diluted 1:10 with assay buffer(50 mM Tris, 150 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, pH 7.40) andhomogenised for 30 seconds with an Ultra-Turrax. 230 μl of thehomogenised product are incubated for 180 minutes at ambient temperaturewith 50 pM ¹²⁵I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham)and increasing concentrations of the test substances in a total volumeof 250 μl. The incubation is ended by rapid filtration through GF/Bglass fibre filters treated with polyethyleneimine (0.1%) using a cellharvester. The protein-bound radioactivity is measured using a gammacounter. Non-specific binding is defined as the bound radioactivityafter the presence of 1 μM human CGRP-alpha during incubation.

The concentration binding curves are analysed using computer-aidednon-linear curve fitting.

The compounds mentioned hereinbefore show Ki values ≦50 μM in the testdescribed.

B. CGRP Antagonism in SK-N-MC Cells

SK-N-MC cells (1 million cells) are washed twice with 250 μl incubationbuffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4)and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP(10 μl) as agonist in increasing concentrations (10⁻¹¹ to 10⁻⁶ M), oradditionally the substance in 3 to 4 different concentrations, themixture is incubated for another 15 minutes.

Intracellular cAMP is then extracted by the addition of 20 μl of 1M HCland centrifugation (2000×g, 4° C., for 15 minutes). The supernatants arefrozen in liquid nitrogen and stored at −20° C.

The cAMP contents of the samples are determined by radioimmunoassay(Messrs. Amersham) and the pA₂ values of antagonistically actingsubstances are determined graphically.

The compounds according to the invention exhibit CGRP-antagonisticproperties in the in vitro test model described, in a dosage rangebetween 10⁻¹² and 10⁻⁴ M.

To demonstrate that the compounds of general formula I exhibit good tovery good CGRP-antagonistic activities with different structuralelements, the following Table gives the K_(i) values obtained accordingto the test procedure described above. It should be noted that thecompounds were selected for their different structural elements and notin order to emphasise specific compounds:

Example K_(i) [nM] (1) 6 (2) 27

Indications

In view of their pharmacological properties the compounds according tothe invention and the salts thereof with physiologically acceptableacids are thus suitable for the acute and prophylactic treatment ofheadaches, particularly migraine or cluster headaches and tensionheadaches. Moreover, the compounds according to the invention also havea positive effect on the following diseases: non-insulin-dependentdiabetes mellitus (“NIDDM”), cardiovascular diseases, morphinetolerance, diarrhoea caused by clostridium toxin, skin diseases,particularly thermal and radiation-induced skin damage includingsunburn, lichen, pruritis, pruritic toxidermies and severe itching,inflammatory diseases, e.g. inflammatory diseases of the joints(osteoarthritis, rheumatoid arthritis, neurogenic arthritis),generalised soft-tissue rheumatism (fibromyalgia), neurogenicinflammation of the oral mucosa, inflammatory lung diseases, allergicrhinitis, asthma, COPD, diseases accompanied by excessive vasodilatationand resultant reduced blood supply to the tissues, e.g. shock andsepsis, chronic pain, e.g. diabetic neuropathies, neuropathies inducedby chemotherapy, HIV-induced neuropathies, postherpetic neuropathies,neuropathies induced by tissue trauma, trigeminal neuralgias,temporomandibular dysfunctions, CRPS (complex regional pain syndrome),back pain, and visceral complaints, such as e.g. irritable bowelsyndrome (IBS) and inflammatory bowel syndrome. In addition, thecompounds according to the invention have a general pain-relievingeffect. The symptoms of menopausal hot flushes caused by vasodilatationand increased blood flow in oestrogen-deficient women andhormone-treated patients with prostate carcinoma and castrated men arefavourably affected by the CGRP antagonists of the present applicationin a preventive and acute-therapeutic capacity, this therapeuticapproach being distinguished from hormone replacement by the absence ofside effects.

The dosage required to achieve a corresponding effect is conveniently0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of bodyweight, when administered intravenously or subcutaneously, and 0.01 to10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight whenadministered orally, nasally or by inhalation, 1 to 3× a day in eachcase.

If the treatment with CGRP antagonists and/or CGRP release inhibitors isgiven as a supplement to conventional hormone replacement, it isadvisable to reduce the doses specified above, in which case the dosagemay be from 1/5 of the lower limits mentioned above up to 1/1 of theupper limits specified.

The invention further relates to the use of the compounds according tothe invention as valuable adjuvants for the production and purification(by affinity chromatography) of antibodies as well as in RIA and ELISAassays, after suitable radioactive labelling, for example by tritiationof suitable precursors, for example by catalytic hydrogenation withtritium or replacing halogen atoms with tritium, and as a diagnostic oranalytical adjuvant in neurotransmitter research.

Combinations

Categories of active substance which may be used in combination includee.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokininantagonists, anticonvulsants, histamine-H1-receptor antagonists,β-blockers, α-agonists and α-antagonists, ergot alkaloids, mildanalgesics, non-steroidal antiphlogistics, corticosteroids, calciumantagonists, 5-HT_(1B/1D)-agonists or other anti-migraine agents whichmay be formulated together with one or more inert conventional carriersand/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions, solutions, metered dose aerosols or suppositories.

Thus other active substances which may be used for the combinationsmentioned above include for example the non-steroidal antiinflammatoriesaceclofenac, acemetacin, acetylsalicylic acid, acetaminophen(paracetamol), azathioprine, diclofenac, diflunisal, fenbufen,fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen,leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone,piroxicam, sulphasalazine, zomepirac or the pharmaceutically acceptablesalts thereof as well as meloxicam and other selective COX2-inhibitors,such as for example rofecoxib, valdecoxib, parecoxib, etoricoxib andcelecoxib, as well as substances that inhibit earlier or later stages ofprostaglandin synthesis or prostaglandin receptor antagonists such ase.g. EP2-receptor antagonists and IP-receptor antagonists.

It is also possible to use ergotamine, dihydroergotamine,metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine,chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox,gabapentin, pregabalin, duloxetine, topiramate, riboflavin, montelukast,lisinopril, micardis, prochloroperazine, dexamethasone, flunarizine,dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol,atenolol, clonidine, indoramin, carbamazepine, phenyloin, valproate,amitryptiline, imipramine, venlafaxine, lidocaine or diltiazem and other5-HT_(1B/1D)-agonists such as, for example, almotriptan, avitriptan,eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan andzolmitriptan.

Furthermore, CGRP antagonists with vanilloid receptor antagonists, suchas e.g. VR-1 antagonists, glutamate receptor antagonists, such as e.g.MGlu5 receptor antagonists, mGlu1 receptor antagonists, iGlu5 receptorantagonists, AMPA receptor antagonists, purine receptor blockers, suchas e.g. P2X3 antagonists, NO-synthase inhibitors, such as e.g. INOSinhibitors, calcium channel blockers, such as e.g. PQ-type blockers,N-type blockers, potassium channel openers, such as e.g. KCNQ channelopeners, sodium channel blockers, such as e.g. PN3 channel blockers,NMDA receptor antagonists, acid-sensing ion channel antagonists, such ase.g. ASIC3 antagonists, bradykinin receptor antagonists such as e.g. B1receptor antagonists, cannabinoid receptor agonists, such as e.g. CB2agonists, CB1 agonists, somatostatin receptor agonists, such as e.g.Sst2 receptor agonists may be added.

The dosage of these active substances is expediently 1/5 of the lowestusually recommended dose to 1/1 of the normally recommended dose, i.e.for example 20 to 100 mg of sumatriptan.

Formulations

The compounds prepared according to the invention may be administeredeither on their own or optionally in combination with other activesubstances for the treatment of migraine by intravenous, subcutaneous,intramuscular, intraarticular, intrarectal, intranasal route, byinhalation, topically, transdermally or orally, while aerosolformulations are particularly suitable for inhalation. The combinationsmay be administered either simultaneously or sequentially.

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised bythe content of one or more compounds of formula I according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula I areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules. Suitable suppositories may be made forexample by mixing with carriers provided for this purpose, such asneutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula I are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula I have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

EXPERIMENTAL SECTION

As a rule IR, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared. Unless stated otherwise, R_(f) values are determinedusing ready-made TLC silica gel plates 60 F254 (E. Merck, Darmstadt,Item no. 1.05714) without chamber saturation.

The ratios given for the eluants relate to units by volume of theparticular solvents. The units by volume given for NH₃ relate to aconcentrated solution of NH₃ in water.

Unless stated otherwise, the acid, base and salt solutions used inworking up the reaction solutions are aqueous systems of the specifiedconcentrations. Silica gel made by Millipore (MATREX™, 35-70 μm) is usedfor chromatographic purifications.

The HPLC data provided are measured under the parameters listed belowand using the columns mentioned:

Columns used:

(column temperature: 30° C.; injection volume: 5 μL; detection at 254nm)

S1 Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 3.5 μm;4.6 × 75 mm S2 Zorbax column (Agilent Technologies), SB (Stable Bond)C18; 1.8 μm; 3.0 × 30 mm S3 Zorbax column (Agilent Technologies), SB(Stable Bond) C18; 5 μm; 4.6 × 75 mm S4 Xbridge (Waters) C18; 3.0 × 30mm, 2.5 μm S5 Sunfire C18 (Waters); 3.5 μm; 4.6 × 75 mm S6 Symmetry C18(Waters); 4.6 × 75 mm, 3.5 μmSolvents used:

solvent A: water (with 0.1% formic acid), solvent B: acetonitrile (with0.1% formic acid), solvent C: water (with 0.1% ammonia), solvent D:acetonitrile (with 0.1% ammonia); the percentages are based on the totalvolume

Gradients:

time gradient [min] % A % B G1 0.00 95 5 (1.6 mL/min) 0.10 95 5 1.75 595 1.90 5 95 1.95 95 5 2.00 95 5 G2 0.00 95 5 (1.6 mL/min) 4.50 10 905.00 10 90 5.50 95 5 G3 0.00 95 5 (1.6 mL/min) 4.00 50 50 4.50 10 905.00 10 90 5.50 95 5 G4 0.00 95 5 (1.6 mL/min) 1.00 10 90 2.50 50 502.75 95 5 G5 0.00 95 5 (1.6 mL/min) 2.00 10 90 5.00 10 90 5.50 95 5 timegradient [min] % C % D G6 0.00 95 5 (1.4 mL/min) 1.80 10 90 2.00 10 902.20 95 5 G7 0.00 95 5 (1.6 mL/min) 2.00 50 50 2.25 10 90 2.50 10 902.75 95 5Methods:

column gradient method A S1 G1 method B S2 G1 method C S1 G2 method D S1G3 method E S2 G4 method F S1 G5 method G S4 G6 method H S2 G7 method IS5 G3 method K S5 G2 method L S6 G3 method M S6 G8

In preparative HPLC purifications as a rule the same gradients are usedas were used to obtain the analytical HPLC data. The products arecollected under mass control, the fractions containing product arecombined and freeze-dried.

In the absence of any more information regarding the configuration, itis unclear whether there are pure enantiomers involved or whetherpartial or even total racemisation has taken place.

The following abbreviations are used in the test descriptions:

-   AcOH acetic acid-   BINAP 2,2′-bis(diphenylphosphino-)1,1′-binaphthyl-   BOC tert-butyloxycarbonyl-   CDI 1,1′-carbonyldiimidazole-   cyc cyclohexane-   DCM dichloromethane-   DIPE diisopropylether-   DIPEA diisopropylethylamine-   DMF N,N-dimethylformamide-   of th. of theory-   d-water demineralised water-   EI electron impact ionisation (in MS)-   ESI electron spray ionisation (in MS)-   EtOAc ethyl acetate-   EtOH ethanol-   el. eluant-   HCl hydrochloric acid-   HCOOH formic acid-   HPLC High Performance Liquid Chromatography-   HPLC-MS HPLC coupled mass spectrometry-   HV high vacuum-   i.vac. under vacuum (in vacuo)-   conc. concentrated-   MeOH methanol-   MS mass spectrometry-   MW molecular weight [g/mol]-   NaOH sodium hydroxide-   NH₄OH ammonium hydroxide (aqueous ammonia solution, 30%)-   NMP N-methyl-2-pyrrolidine-   Pd₂ dba₃ bis(dibenzylideneacetone) palladium-(0)-   PE petroleum ether-   R_(f) retention index (in TLC)-   RT ambient temperature-   R_(t) retention time (in HPLC)-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   DC drying cupboard-   CAD circulating air dryer    Preparation of the Starting Compounds

Intermediate 1 6-chloropyrimidine-4-carboxylic acid chloride

Step 1: 6-hydroxypyrimidine-4-carboxylic acid

63.5 g (287 mmol) sodium diethyl-oxalacetate and 30.2 g (287 mmol)formamidine acetate were added to 24.1 g (0.597 mol) NaOH in 3.6 Lwater. The mixture was stirred overnight at RT. Then activated charcoalwas added and the mixture was refluxed for 1 h. It was filtered whilehot and after cooling acidified with aqueous HCl. The solution wasconcentrated to dryness by rotary evaporation. The residue contained thedesired product and was used in the next step without any furtherpurification.

Yield: 83.0 g

Step 2: 6-chloropyrimidine-4-carboxylic acid chloride

50 g (0.352 mol) 6-hydroxypyrimidine-4-carboxylic acid was taken and 500mL phosphorus oxychloride was added thereto. Then phosphoruspentachloride was added batchwise with stirring 150 g (0.720 mol). Thereaction mixture was refluxed for 5 h. The phosphorus oxychloride wasdistilled off and the residue was purified by vacuum distillationthrough a column.

Yield: 52 (83% of theoretical)

EI-MS: m/z=176/178/180 (M)⁺ (2 Cl)

Intermediate 2 4-methyl-3H-benzoxazol-2-one

25.0 g (200 mmol) 2-amino-m-cresol and 70.4 ml. (400 mmol) DIPEA wereplaced in 1.0 L DCM and cooled to 0° C. A solution of 38.0 g (227 mmol)1.1′-carbonyldiimidazole was added dropwise thereto over 30 min. Themixture was stirred for 30 min at 0° C., then overnight at RT. Afterevaporation of the reaction mixture i.vac. down to half its volume theaqueous phase was washed with water (2×250 mL), 1M aqueous potassiumhydrogen sulphate solution (1×250 mL) and again water (1×250 mL). Theorganic phase was evaporated down i.vac. The crude product remaining asa solid was triturated with a mixture of diethyl ether and PE, theprecipitated solid was suction filtered, washed with PE and dried i.vac.

Yield: 25.0 g (86% of theoretical)

ESI-MS: m/z=150(M+H)⁺

R_(t) (HPLC)=2.67 min (Method C)

Intermediate 36-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one

2.34 g (13.2 mmol) 6-chloropyrimidine-4-carbonyl chloride, 8.00 g (60.0mmol) aluminium trichloride and 1.79 g (12.0 mmol)4-methyl-3H-benzoxazol-2-one were heated to 130° C. for 1.5 h. Aftercooling to RT the mixture was mixed with ice water, then extracted withethyl acetate, the organic phase was dried on sodium sulphate andevaporated down i.vac. The crude product left as a solid was trituratedwith diethyl ether, suction filtered and dried in the air.

Yield: 2.00 g (52% of theoretical)

ESI-MS: m/z=290/292 (M+FI)⁺ (Cl)

R_(t) (HPLC)=3.17 min (Method C)

Intermediate 46-(6-Chlorpyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one

0.35 g (8.0 mmol) sodium hydride (55%, suspension in mineral oil) wereadded to 2.2 g (7.6 mmol)6-(6-chloropyrimidin-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mLDMF. The reaction mixture was stirred for 30 min at RT. Then 0.95 mL(15.0 mmol) iodomethane were added and the mixture was stirred for 1 hat RT. The reaction mixture was combined with ice water and the aqueousphase was extracted several times with EtOAc. The combined organicphases were dried on sodium sulphate, filtered and evaporated to drynessby rotary evaporation. The residue was triturated with diethyl ether,suction filtered and dried.

Yield: 1.6 g (69% of theoretical)

ESI-MS: m/z=304/306 (M+H)⁺

R_(t) (HPLC): 3.55 min (method C)

Intermediate 5 1′H-spiro[piperidin-4,4′-quinazolin]-2′(3′H)-one

This compound and its precursors were synthesised as described inWO2003/104236.

ESI-MS: m/z=218 (M+H)⁺

R_(f): 0.08 (silica gel, DCM/cyc/MeOH/NH₄OH=70/15/15/2)

Intermediate 6 spiro[benzo[d][1,3]oxazin-4,4′-piperidin]-2(1H)-onehydrochloride

This compound and its precursors were synthesised as described in U.S.Pat. No. 6,436,962.

ESI-MS: m/z=219 (M+H)⁺

R_(f): 0.14 (silica gel, DCM/cyc/MeOH/NH₄OH=70/15/15/2)

Intermediate 7spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride

Step 1: tert-butyl (6-chloro-pyridin-2-yl)-carbamate

Under a nitrogen atmosphere a solution of 32.7 g (0.150 mol)BOC-anhydride in 100 mL THF was added dropwise at RT to a mixture of17.4 g (0.135 mol) 6-chloropyridin-2-ylamine and 300 mL (0.300 mol) of asodium hexamethyldisilazide solution (1M in THF) in 200 mL of THF. Thereaction mixture was stirred overnight at RT and evaporated down i.vac.The residue was stirred between EtOAc and 1N aqueous hydrochloric acidsolution. The organic phase was separated off and the aqueous phase wasextracted with EtOAc. The combined organic phases were washed withsaturated sodium hydrogen carbonate solution, dried and evaporated down.The residue was recrystallised from EtOH, the solid was suction filteredand dried.

Yield: 29.2 g (95% of theoretical)

ESI-MS: m/z=228 (M+)

R_(t)(HPLC): 1.70 min (method B)

Step 2:benzyl-7′-chloro-2′-oxo-1′,2′-dihydrospiro[piperidin-4,4′-pyrido[2,3d][1,3]oxazin]-1-carboxylate

Under a nitrogen atmosphere 26.0 mL (173 mmol)N,N,N,N-tetramethylene-ethylenediamine in 180 mL THF were cooled to −20°C. and combined with 70.0 mL (175 mmol) 2.5 M butyllithium solution.After 30 minutes' stirring the reaction mixture was cooled to −78° C.,and at this temperature 17.8 g (78.0 mmol) tert-butyl(6-chloro-pyridin-2-yl)-carbamate in 120 mL THF were slowly addeddropwise. The reaction mixture was stirred for 2.5 h at −78° C. and thencombined with 27.2 g (117 mmol) Cbz-protected piperidone in 60 mL ofTHF. After one hour at −78° C. the mixture was heated to RT and thenstirred for 18 h at 40° C. The reaction mixture was decomposed by thedropwise addition of 150 mL saturated sodium hydrogen carbonatesolution. Then it was extracted with DCM. The combined organic phaseswere washed with water, dried and evaporated down. The residue wastriturated with PE/EtOAc (1/1), the precipitate formed was suctionfiltered, washed with PE/EtOAc (1/1) and dried.

Yield: 16.4 g (54% of theoretical)

ESI-MS: m/z=388 (M+H)⁺

R_(t)(HPLC): 1.57 min (method B)

Step 3: Spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-onehydrochloride

16.4 g (42.0 mmol)benzyl-7′-chloro-2′-oxo-1′,2′-dihydrospiro[piperidin-4,4′-pyrido[2,3d][1,3]oxazin]-1-carboxylateand 2.00 g palladium on charcoal (Pd/C 10%) in 500 mL EtOH werehydrogenated for 6 h at RT in a hydrogen atmosphere. Then 1.0 gpalladium on charcoal (Pd/C 10%) were added and the reaction mixture washydrogenated for a further 3 h at RT in a hydrogen atmosphere. Afterfiltration of the reaction mixture the solvent was eliminated i.vac. Theresidue was triturated with EtOH, the precipitate formed was suctionfiltered, washed with EtOH and dried.

Yield: 5.40 g (50% of theoretical)

ESI-MS: m/z=220 (M+H)⁺

R_(t)(HPLC): 0.90 min (method C)

Intermediate 86-(6-chloro-2-methyl-pyrimidin-4-carbonyl)-4-methyl-3H-benzoxazol-2-one

Step 1: 6-chloro-2-methyl-pyrimidine-4-carboxylic acid chloride

2.00 g (13.0 mmol) 6-hydroxy-2-methylpyrimidin-4-carboxylic acid wererefluxed for 2 h with 11.9 mL (130 mmol) phosphorus oxychloride. Aftercooling to RT, 2.70 g (13.0 mmol) phosphorus-(V)-chloride were added andthe mixture was boiled for 2 h. The reaction mixture was cooled to RTcooled, evaporated to dryness i.vac. And co-evaporated twice withtoluene. The residue was triturated several times with DCM and theexcess DCM was decanted off. The combined DCM phases were evaporateddown and the residue was further reacted as the crude product.

Yield: 2.48 g (quantitative)

Step 2:6-(6-chloro-2-methyl-pyrimidin-4-carbonyl)-4-methyl-3H-benzoxazol-2-one

2.48 g (13.0 mmol) 6-chloro-2-methyl-pyrimidine-4-carboxylic acidchloride, 1.94 g (13.0 mmol) 4-methyl-3H-benzoxazol-2-one and 6.93 g(52.0 mmol) aluminium trichloride were heated to 125° C. with stirringfor 1.5 h. The mixture was combined with ice water and the precipitateformed was suction filtered and washed with water. Then the precipitatewas dissolved in MeOH/DCM and suction filtered through silica gel. Thefiltrate was evaporated down and the residue was purified by flashchromatography. The fractions containing the product were combined,evaporated down and triturated with diethyl ether. The precipitate wassuction filtered, washed with diethyl ether and dried i. vac.

Yield: 0.600 g (15% of theoretical)

ESI-MS: m/z=304 (M+H)⁺

R_(t)(HPLC): 1.42 min (method B)

Intermediate 96-(6-chloro-2-methyl-pyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one

59 mg (1.4 mmol) sodium hydride (55%, suspension in mineral oil) wereadded at RT to 0.37 g (1.2 mmol)6-(6-chloro-2-methyl-pyrimidin-4-carbonyl)-4-methyl-3H-benzoxazol-2-onein 5.0 mL. DMF. The reaction mixture was stirred for 30 min at RT. Then0.10 ml. (1.60 mmol) iodomethane were added and the mixture was stirredfor 1 h at RT. Then another 0.10 ml. (1.60 mmol) iodomethane were addedand the mixture was stirred overnight at RT. The reaction mixture wasdiluted with ice water and the precipitate formed was suction filtered.The residue was washed with water and dried i. vac.

Yield: 0.37 g (96% of theoretical)

ESI-MS: m/z=318 (M+H)⁺

R_(t)(HPLC): 1.53 min (method B)

Intermediate 10(6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanone

Step 1: 7-methyl-2,3-dihydro-benzofuran-3-ol

Under a nitrogen atmosphere 0.945 g (7.35 mmol) trimethylsulphoxoniumchloride were placed in 20 mL THF and combined batchwise with 0.300 g(7.50 mmol) sodium hydride (55%, suspension in mineral oil). Thereaction mixture was refluxed for 2 h. Then 1.00 g (7.35 mmol)2-hydroxy-3-methylbenzaldehyde in 20 ml. THF were added dropwise to thereaction mixture and refluxed overnight. Then PE was added and thesuspension obtained was filtered. The filtrate was evaporated downi.vac. and purified by flash chromatography. The fractions containingthe product were combined and evaporated down.

Yield: 0.615 g (56% of theoretical)

ESI-MS: m/z=133 (M−H₂O+H)⁺

R_(t) (HPLC): 1.09 min (method B)

Step 2: 7-methyl-2,3-dihydro-benzofuran

Under a nitrogen atmosphere 0.610 g (4.06 mmol)7-methyl-2,3-dihydro-benzofuran-3-ol in 5 mL acetic acid were refluxedwith 770 μL. (8.16 mmol) acetic anhydride for 2 h. After cooling to RT,60 mg palladium on charcoal (Pd/C 10%) were added and the mixture washydrogenated for 3.5 h under a hydrogen atmosphere (3 bar). The catalystwas filtered off and the solvent was evaporated down.

Yield: 0.350 g (64% of theoretical)

MS: m/z=134 (M⁺)

Step 3:(6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanone

0.396 g (2.24 mmol) 6-chloropyrimidin-4-carboxylic acid chloride and0.328 g (2.46 mmol) aluminium trichloride in 10 mL DCM were stirred for20 min at RT. Then 0.300 g (2.24 mmol) 7-methyl-2,3-dihydro-benzofuranin DCM were added dropwise to the reaction mixture and this was stirredfor 1.5 h at RT. After the addition of water and DCM to the reactionmixture the phases were separated and the aqueous phase was extractedwith DCM. The combined organic phases were washed with saturated aqueoussodium hydrogen carbonate solution, dried on sodium sulphate, filteredand evaporated down i.vac.

Yield: 0.550 g (62% of theoretical)

purity: 70%

ESI-MS: m/z=275/277 (Cl) (M+H)⁺

R_(t) (HPLC): 1.54 min (method B)

Intermediate 115-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

This compound was synthesised as described in WO2006/029153.

ESI-MS: m/z=252 (M+H)⁺

R_(f) (DC)=0.4 (10% methanol/chloroform)

Intermediate 12(6-chloro-pyrimidin-4-yl)-(2,3-difluoro-phenyl)-methanone

Step 1: S-phenyl 6-chloro-pyrimidin-4-carbothionate

1.58 mL (15.4 mmol) thiophenol and 2.75 mL (16.08 mmol) DIPEA were addedat 0° C. to 3.00 g (16.1 mmol) 6-chloropyrimidine-4-carboxylic acidchloride in 100 mL DCM and stirred for 1 h at 0° C. and 1 h at RT. Thenthe reaction mixture was diluted with DCM and washed with saturatedsodium hydrogen carbonate solution and water. The organic phase wasdried on sodium sulphate, filtered, additionally filtered through silicagel and washed with DCM. The filtrate was then evaporated down.

Yield: 3.80 g (99% of theoretical)

MS: m/z=250/252 (Cl) (M⁺)

R_(t) (HPLC): 2.95 min (method F)

Step 2: (6-chloro-pyrimidin-4-yl)-(2,3-difluoro-phenyl)-methanone

Argon was piped through 0.50 g (2.0 mmol) S-phenyl6-chloro-pyrimidine-4-carbothionate, 0.38 g (2.4 mmol)2,3-difluorophenylboric acid and 0.46 g (2.4 mmol)copper-thiophene-2-carboxylate in 25 mL THF for 3 min and then 46 mg(0.05 mmol) Pd₂dba₃ and 35 μL (0.20 mmol) triethylphosphite were added.The reaction mixture was stirred for another 48 h at RT, then theprecipitate formed was filtered off and the filtrate was evaporateddown. The residue was purified by flash chromatography.

Yield: 0.47 g (83% of theoretical)

purity: 90%

ESI-MS: m/z=255/257 (Cl) (M+H)⁺

R_(t) (HPLC): 4.23 min (method C)

Preparation of the End Compounds

Example 14-methyl-6-(6-(2′-oxo-2′,3′-dihydro-1′H-spiro[piperidin-4,4′-quinazolin]-1-yl)pyrimidine-4-carbonyl)benzo[d]oxazol-2(3H)-one

144 mg (0.500 mmol)6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one, 108 mg(0.500 mmol) 1′H-spiro[piperidin-4,4′-quinazolin]-2′(3′H)-one and 0.174mL (1.00 mmol) DIPEA were combined in 5.0 mL DMF and stirred overnightat RT. The reaction mixture was purified by preparative HPLC, thefractions containing the product were combined and the organic solventwas eliminated i.vac. The aqueous phase was neutralised by the additionof 4N aqueous NaOH solution. The product precipitated as a solid wasfiltered off, washed with water and dried.

Yield: 130 mg (55% of theoretical)

ESI-MS: m/z=471 (M+H)⁺

R_(t) (HPLC)=2.55 min (Method C)

Example 24-methyl-6-(6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carbonyl)benzo[d]oxazol-2(3H)-one

144 mg (0.500 mmol)6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one, 126 mg(0.500 mmol)5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneand 16.1 mg (0.100 mmol) benzenesulphonic acid were combined in 5.0 mL2-pentanol and refluxed for 4 h. The reaction mixture was evaporateddown, the residue was triturated with PE, suction filtered and washedwith PE. The residue was purified by preparative HPLC, the fractionscontaining the product were combined and the organic solvent waseliminated i.vac. The aqueous phase was neutralised by the addition of1N aqueous NaOH solution. The product precipitated as a solid wasfiltered off, washed with water and dried.

Yield: 85 mg (34% of theoretical)

ESI-MS: m/z=505 (M+H)⁺

R_(t) (HPLC)=2.88 min (Method C)

Example 33,4-dimethyl-6-(6-(2′-oxo-2′,3′-dihydro-1′H-spiro[piperidin-4,4′-quinazolin]-1-yl)pyrimidin-4-carbonyl)benzo[d]oxazol-2(3H)-one

87.0 mg (0.400 mmol) 1′H-spiro[piperidin-4,4′-quinazolin]-2′(3′H)-one,122 mg (0.400 mmol)6-(6-chloropyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and0.140 mL (0.800 mmol) DIPEA were combined in 3.0 mL DMF and stirred for48 h at RT. The reaction mixture was diluted with MeOH, the precipitatewas suction filtered, washed with diethyl ether and dried.

Yield: 184 mg (95% of theoretical)

ESI-MS: m/z=485 (M+H)⁺

R_(t) (HPLC): 1.14 min (method A)

Example 43,4-dimethyl-6-(6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidin-4-carbonyl)benzo[d]oxazol-2(3H)-one

16.0 mg (0.100 mmol) benzenesulphonic acid were added to 126 mg (0.500mmol)5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneand 152 mg (0.500 mmol)6-(6-chloro-pyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one in5.0 mL of 2-pentanol and boiled for 4 h. The reaction mixture wasevaporated down and purified by preparative HPLC. The fractionscontaining the product were combined, the organic solvent was eliminatedi.vac. and the aqueous phase remaining was neutralised with 1M aqueousNaOH solution. The product precipitated as a solid was suction filtered,washed with water and dried i. vac.

Yield: 110 mg (42% of theoretical)

ESI-MS: m/z=519 (M+H)⁺

R_(t) (HPLC)=1.3 min (method B)

Example 51′-(6-(3,4-dimethyl-2-oxo-2.3-dihydrobenzo[d]oxazol-6-carbonyl)pyrimidin-4-yl)spiro[benzo[d][1,3]oxazin-4,4′-piperidin]-2(1H)-one

102 mg (0.400 mmol) spiro[benzo[d][1,3]oxazin-4,4′-piperidin]-2(1H)-onhydrochloride, 122 mg (0.400 mmol)6-(6-chloropyrimidin-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.210mL (1.20 mmol) DIPEA were combined in 3.0 mL DMF and stirred for 48 h.The mixture was purified by preparative HPLC-MS. The fractionscontaining the product were combined, the organic solvent was eliminatedi.vac. and the aqueous phase remaining was neutralised with 4M aqueousNaOH solution. The product precipitated as a solid was suction filtered,washed with water and dried in the CAD.

Yield: 90 mg (46% of theoretical)

ESI-MS: m/z=486 (M+H)⁺

R_(t) (HPLC): 1.25 min (method B)

Example 61-(6-(3,4-dimethyl-2-oxo-2.3-dihydrobenzo[d]oxazol-6-carbonyl)pyrimidin-4-yl)spiro[piperidin-4,4′-pyrido[2.3-d][1,3]oxazin]-2′(1′H)-one

55 mg (0.21 mmol)spiro[piperidin-4,4′-pyrido[2.3-d][1,3]oxazin]-2′(1′H)-onehydrochloride, 65 mg (0.21 mmol)6-(6-chloropyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and0.15 mL (0.84 mmol) DIPEA were combined in 1.8 mL DMF and stirredovernight at RT. Then the reaction mixture was purified by preparativeHPLC-MS. The fractions containing the product were combined andfreeze-dried.

Yield: 73.0 mg (70% of theoretical)

ESI-MS: m/z=487 (M+H)⁺

R_(t) (HPLC): 2.60 min (method C)

Example 71-(6-(3,4-dimethyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-carbonyl)-2-methylpyrimidin-4-yl)spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one

77 mg (0.30 mmol)spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-onehydrochloride, 88 mg (0.28 mmol)6-(6-chloro-2-methyl-pyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-oneand 0.17 mL (1.0 mmol) DIPEA were combined in 2 mL DMF and stirredovernight at RT. Then the reaction mixture was purified by preparativeHPLC-MS. The fractions containing the product were combined and theorganic solvent was evaporated down. The residue was neutralised with 4Naqueous sodium hydroxide solution. The precipitate formed was suctionfiltered, washed with water and dried i. vac.

Yield: 53 mg (35% of theoretical)

ESI-MS: m/z=501 (M+H)⁺

R_(t) (HPLC): 1.07 min (method B)

Example 85-(6-(7-methyl-2.3-dihydrobenzofuran-5-carbonyl)pyrimidin-4-ylamino)-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A spatula tip of benzenesulphonic acid was added to 70 mg (0.28 mmol)5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneand 0.10 g (0.26 mmol)(6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanonein 2 mL 1-pentanol and the mixture was stirred at 85° C. for 1 h. Thereaction mixture was evaporated down, taken up in DMF, acidified with afew drops of hydrochloric acid and purified by preparative HPLC. Thefractions containing the product were combined and freeze-dried.

Yield: 60 mg (48% of theoretical)

ESI-MS: m/z=490 (M+H)⁺

R_(t) (HPLC): 1.39 min (method B)

Example 95-(6-(2,3-difluorobenzoyl)pyrimidin-4-ylamino)-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

70 mg (0.28 mmol)5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,80 mg (0.28 mmol)(6-chloro-pyrimidin-4-yl)-(2.3-difluoro-phenyl)-methanone and 60 μLDIPEA in 600 μL dimethylsulphoxide were stirred for 1 h at 80° C. Aftercooling the reaction mixture was combined with approx. 10 mL ice water.The liquid was decanted off and the residue was dissolved in DCM andMeOH. After drying with sodium sulphate the mixture was filtered and thesolvent was evaporated down. The residue was triturated with ether,suction filtered and dried.

Yield: 82 mg (60% of theoretical)

ESI-MS: m/z=470 (M+H)⁺

R_(t) (HPLC): 3.97 min (method C)

The following Examples describe the preparation of pharmaceuticalformulations that contain as active substance any desired compound ofgeneral formula I:

Example I

Capsules for Powder Inhalation Containing 1 mg of Active Ingredient

Composition:

1 capsule for powder inhalation contains:

active ingredient  1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg71.0 mgMethod of Preparation:

The active ingredient is ground to the particle size required forinhaled substances. The ground active ingredient is homogeneously mixedwith the lactose. The mixture is transferred into hard gelatinecapsules.

Example II

Inhalable Solution for Respimat® Containing 1 mg of Active Ingredient

Composition:

1 puff contains:

active ingredient 1.0 mg benzalkonium chloride 0.002 mg disodium edetate0.0075 mg purified water ad 15.0 μlMethod of Preparation:

The active ingredient and benzalkonium chloride are dissolved in waterand transferred into Respimat® cartridges.

Example III

Inhalable Solution for Nebulisers Containing 1 mg of Active Ingredient

Composition:

1 vial contains:

active ingredient 0.1 g sodium chloride 0.18 g benzalkonium chloride0.002 g purified water ad 20.0 mlMethod of Preparation:

The active ingredient, sodium chloride and benzalkonium chloride aredissolved in water.

Example IV

Propellant Gas-Operated Metered Dose Aerosol Containing 1 mg of ActiveIngredient

Composition:

1 puff contains:

active ingredient 1.0 mg lecithin 0.1% propellant gas ad 50.0 μlMethod of Preparation:

The micronised active ingredient is homogeneously suspended in themixture of lecithin and propellant gas. The suspension is transferredinto a pressurised container with a metering valve.

Example V

Nasal Spray Containing 1 mg of Active Ingredient

Composition:

active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium chloride0.025 mg disodium edetate 0.05 mg purified water ad 0.1 mlMethod of Preparation:

The active ingredient and the excipients are dissolved in water andtransferred into a suitable container.

Example VI

Injectable Solution Containing 5 mg of Active Substance Per 5 ml

Composition:

active substance 5 mg glucose 250 mg human serum albumin 10 mgglycofurol 250 mg water for injections ad 5 mlPreparation:

Glycofurol and glucose are dissolved in water for injections (WfI);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with WfI; transferred into ampoulesunder nitrogen gas.

Example VII

Injectable Solution Containing 100 mg of Active Substance Per 20 ml

Composition:

active substance 100 mg monopotassium dihydrogen phosphate = KH₂PO₄ 12mg disodium hydrogen phosphate = Na₂HPO₄*2H₂O 2 mg sodium chloride 180mg human serum albumin 50 mg Polysorbate 80 20 mg water for injectionsad 20 mlPreparation:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate anddisodium hydrogen phosphate are dissolved in water for injections (WfI);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with WfI; transferred intoampoules.

Example VIII

Lyophilisate Containing 10 mg of Active Substance

Composition:

Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg waterfor injections ad 2 mlPreparation:

Mannitol is dissolved in water for injections (WfI); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with WfI; transferred into vials; freeze-dried.

Solvent for Lyophilisate:

Polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad10 mlPreparation:

Polysorbate 80 and mannitol are dissolved in water for injections (WfI);transferred into ampoules.

Example IX

Tablets Containing 20 mg of Active Substance

Composition:

active substance 20 mg lactose 120 mg  corn starch 40 mg magnesiumstearate  2 mg Povidone K 25 18 mgPreparation:

Active substance, lactose and corn starch are homogeneously mixed;granulated with an aqueous solution of Povidone; mixed with magnesiumstearate; compressed in a tablet press; weight of tablet 200 mg.

Example X

Capsules Containing 20 mg Active Substance

Composition:

active substance 20 mg corn starch 80 mg highly dispersed silica  5 mgmagnesium stearate 2.5 mg Preparation:

Active substance, corn starch and silica are homogeneously mixed; mixedwith magnesium stearate; the mixture is packed into size for 3 hardgelatine capsules in a capsule filling machine.

Example XI

Suppositories Containing 50 mg of Active Substance

Composition:

active substance  50 mg hard fat (Adeps solidus) q.s. Ad 1700 mgPreparation:

Hard fat is melted at about 38° C.; ground active substance ishomogeneously dispersed in the molten hard fat; after cooling to about35° C. it is poured into chilled moulds.

Example XII

Injectable Solution Containing 10 mg of Active Substance Per 1 ml

Composition:

active substance 10 mg mannitol 50 mg human serum albumin 10 mg waterfor injections ad 1 mlPreparation:

Mannitol is dissolved in water for injections (WfI); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with WfI; transferred into ampoules under nitrogen gas.

The invention claimed is:
 1. A compound of the general formula I

wherein R¹ denotes a group of general formula IIa or IIb

 and R² denotes H or C₁₋₃-alkyl, or R¹ and R² together with the nitrogenatom to which they are bound denote a group of the formulae IIIa or IIIb

G denotes C—R^(1.1) or N, T denotes N—R^(1.2) or O, R^(1.1)independently of one another denote (a) H, (b) halogen, C₁₋₃-alkyl, —OH,—CN, —O—C₁₋₃-alkyl, —C(O)—O—C₁₋₃-alkyl, C₂₋₄-alkenyl, —C₂₋₄-alkynyl,C₁₋₃-alkyl-S, cyclopropyl, —NH₂, —COOH, —NH—C(O)—O—C₁₋₃-alkyl,—NH—C(O)—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl group or C₁₋₃-alkyl-O— groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(1.2) independently of one another denote H or C₁₋₃-alkyl, R^(1.3)denotes (a) H, F, —CN, C₁₋₃-alkyl, —CO₂—R^(1.3.1) or a C₁₋₃-alkyl groupwherein each methylene group may be substituted by up to two fluorineatoms and each methyl group may be substituted by up to three fluorineatoms, R^(1.3.1) denotes (a) H, (b) C₁₋₆-alkyl, R³ a 6 or 10-memberedaryl group substituted by the groups R^(3.1), R^(3.2) and R^(3.3) or a6-membered heteroaryl group substituted by the groups R^(3.1), R^(3.2)and R^(3.3) which is attached via a carbon atom, R^(3.1) denotes (a) H,(b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N, C₁₋₃-alkyl-C(O)—NH,C₁₋₃-alkyl-S(O₂)—NH, —CN, —OH, —O—C(O)—NH—C₁₋₃-alkyl, (c) C₁₋₄-alkyl,R^(3.1.1)—C₁₋₃-alkylene, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,C₁₋₃-alkyl-S(O)_(m), cyclopropyl, (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O—group wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, (e) —C(O)—R^(3.1.2), (f) —S(O)₂—R^(3.1.3), R^(3.1.1) denotes (a)H, C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl, (R^(3.1.1.1))₂N, a saturated,mono- or diunsaturated 5- or 6-membered heterocyclic group which issubstituted at a nitrogen atom by a group R^(3.1.1.1) and is substitutedat a carbon atom by one or two groups R^(3.1.1.2), or a heteroaryl groupwhich is substituted at a carbon atom by a group R^(3.1.1.2),R^(3.1.1.1) independently of one another denote (a) H, C₁₋₄-alkyl,C₃₋₆-cycloalkyl, (b) heterocyclyl, (c) aryl-C₀₋₃-alkylene orheteroaryl-C₀₋₃-alkylene, R^(3.1.1.2) independently of one anotherdenote (a) H, F, C₁₋₃-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,—CO(O)R^(3.1.1.2.1), H₂N, (C₁₋₄-alkyl)-NH, (C₁₋₄-alkyl)₂N, (b) phenyl orphenyl-CH₂, (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, orR^(3.1.1.2.1) denotes H, C₁₋₆-alkyl, benzyl, R^(3.1.2) denotes—O—C₁₋₃-alkyl, —OH, —NR^(3.1.2.1)R^(3.1.2.2), R^(3.1.2.1) denotes H,C₁₋₃-alkyl, R^(3.1.2.2) denotes H, C₁₋₃-alkyl, R^(3.1.2.1) andR^(3.1.2.2) together may also form a ring which is selected from amongazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,R^(3.1.3) denotes —O—C₁₋₃-alkyl, —NR^(3.1.3.1)R^(3.1.3.2), R^(3.1.3.1)denotes H, C₁₋₃-alkyl, R^(3.1.3.2) denotes H, C₁₋₃-alkyl, R^(3.1.3.1)and R^(3.1.3.2) together may also form a ring which is selected fromamong azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl, R^(3.2) denotes (a) H, (b) halogen, —NH₂, C₁₋₄-alkyl-NH,(C₁₋₄-alkyl)₂N, C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O₂)—NH, —CN, —OH,—O—C(O)—NH—C₁₋₃-alkyl, (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₁₋₃-alkyl-O, C₁₋₃-alkyl-S(O)_(m), cyclopropyl, (d) a C₁₋₃-alkyl orC₁₋₃-alkyl-O— group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, (e) —C(O)—R^(3.2.1), (f) —S(O)₂—R^(3.2.2), R^(3.2.1)denotes —O—C₁₋₃-alkyl, —OH, —NR^(3.2.1.1)R^(3.2.1.2), R^(3.2.1.1)denotes H, C₁₋₃-alkyl, R^(3.2.1.2) denotes H, C₁₋₃-alkyl, R^(3.2.1.1)and R^(3.2.1.2) together may also form a ring which is selected fromamong azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl, R^(3.2.2) denotes —NR^(3.2.2.1)R^(3.2.2.2), R^(3.2.2.1)denotes H, C₁₋₃-alkyl, R^(3.2.2.2) denotes H, C₁₋₃-alkyl, R^(3.2.2.1)and R^(3.2.2.2) together may also form a ring which is selected fromamong azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl, R^(3.3) denotes (a) H, (b) halogen, —NH₂, C₁₋₄-alkyl-NH,(C₁₋₄-alkyl)₂N, C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O₂)—NH, —CN, —OH,—O—C(O)—NH—C₁₋₃-alkyl, (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₁₋₃-alkyl-O, C₁₋₃-alkyl-S(O)_(m), cyclopropyl, (d) a C₁₋₃-alkyl orC₁₋₃-alkyl-O— group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, (e) —C(O)—R^(3.3.1), (f) —S(O)₂—R^(3.3.2), R^(3.3.1)denotes —O—C₁₋₃-alkyl, —OH, —NR^(3.3.1.1)R^(3.3.1.2), R^(3.3.1.1)denotes H, C₁₋₃-alkyl, R^(3.3.1.2) denotes H, C₁₋₃-alkyl, R^(3.3.1.1)and R^(3.3.1.2) together may also form a ring which is selected fromamong azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl, R^(3.3.2) denotes —O—C₁₋₃-alkyl, —NR^(3.3.2.1)R^(3.3.2.2),R^(3.3.2.1) denotes H, C₁₋₃-alkyl, R^(3.3.2.2) denotes H, C₁₋₃-alkyl,R^(3.3.2.1) and R^(3.3.2.2) together may also form a ring which isselected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyland morpholinyl, or R^(3.2) and R^(3.3) together with the carbon atomsto which they are attached form a monounsaturated 5-membered or a mono-or diunsaturated 6-membered heterocyclic group or a 5- to 6-memberedheteroaryl group, wherein the heterocycles mentioned previously maycontain a carbonyl, thiocarbonyl or cyanoimino group adjacent to anitrogen atom, and may optionally be additionally substituted at one ortwo nitrogen atoms by a group R^(3.3.3) in each case and may optionallybe additionally substituted at one or two carbon atoms by one or twogroups R^(3.3.4) in each case, R^(3.3.3) independently of one anotherdenote (a) C₁₋₄-alkyl or (b) C₃₋₆-cycloalkyl, R^(3.3.4) independently ofone another denote (a) C₁₋₄-alkyl or (b) C₃₋₆-cycloalkyl, (c) halogen,CN, —O—C₁₋₃-alkyl, —NH₂, (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, U denotes N,or C—R⁴, V denotes C—R⁵, X denotes N, or CR⁶, Y denotes N or C—R⁷, whiletwo of the previously mentioned groups U, X and Y simultaneously denotea nitrogen atom, R⁴ denotes (a) H, (b) a C₁₋₆-alkyl or C₁₋₃-alkyl-O—group which is substituted in each case by a group R^(4.1), (c)R^(4.2)R^(4.3)N, R^(4.2)R^(4.3)N—C₁₋₃-alkylene, (d) halogen, —CN, —OH,—COOH, C₁₋₃-alkyl-O, C₁₋₃-alkyl-O—C₁₋₃-alkylene, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₄-alkylene, C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene, (e) aC₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.1) denotes H, OH or—O—CH₃, R^(4.2) denotes H or C₁₋₃-alkyl, R^(4.3) denotes H orC₁₋₃-alkyl, or R^(4.2) and R^(4.3) together with the nitrogen atom towhich they are bound denote a 3- to 6-membered heterocyclic group, R⁵denotes (a) H, (b) a C₁₋₆-alkyl or C₁₋₃-alkyl-O— group which issubstituted in each case by a group R^(5.1), (c) —NR^(5.2)R^(5.3),NR^(5.2)R^(5.3)—C₁₋₃-alkylene, (d) halogen, —CN, —OH,C₁₋₃-alkyl-O—C₁₋₃-alkylene, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄-alkylene, C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene, (e)aryl-C₀₋₃-alkylene-O— group, (f) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(5.1) denotes H, OH or —O—CH₃, R^(5.2) denotes H or C₁₋₆-alkyl,R^(5.3) denotes H, C₁₋₆-alkyl or —SO₂—C₁₋₃-alkyl, or R^(5.2) and R^(5.3)together with the nitrogen atom to which they are bound denote a 3- to6-membered heterocyclic group, R⁶ denotes (a) H, (b) a C₁₋₆-alkyl orC₁₋₃-alkyl-O— group which is substituted in each case by a groupR^(6.1), (c) R^(6.2)R^(6.3)N, R^(6.2)R^(6.3)N—C₁₋₃-alkylene, (d)halogen, —CN, —OH, —COOH, C₁₋₃-alkyl-O, C₁₋₃-alkyl-O—C₁₋₃-alkylene,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄-alkylene,C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene, (e) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(6.1) denotes H, OH or —O—CH₃, R^(6.2) denotes H or C₁₋₃-alkyl,R^(6.3) denotes H or C₁₋₃-alkyl, or R^(6.2) and R^(6.3) together withthe nitrogen atom to which they are bound denote a 3- to 6-memberedheterocyclic group, and R⁷ denotes H, halogen or C₁₋₃-alkyl, or atautomer or salt thereof.
 2. compound of the formula I according toclaim 1, wherein R¹ denotes a group of the formula

R^(1.1) denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,—C(O)—O—C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-S, —NH₂, (c)a C₁₋₃-alkyl group or C₁₋₃-alkyl-O— group wherein each methylene groupis substituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, and R^(1.2) denotes (a) H or(b) CH₃, or a tautomer or salt thereof.
 3. A compound of the formula Iaccording to claim 1, wherein R¹ and R² together with the nitrogen atomto which they are bound denote a group of the formula

R^(1.1) denotes (a) H, halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,—C(O)—O—C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-S, —NH₂, aC₁₋₃-alkyl group or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or a tautomer or saltthereof.
 4. A compound of the formula I according to claim 1, wherein R¹denotes a group of the formula

R^(1.1) denotes (a) F, CH₃, —OH, —O—CH₃ or (b) CF₃, or a tautomer orsalt thereof.
 5. A compound of the formula I according to claim 1,wherein R¹ and R² together with the nitrogen atom to which they arebound denote a group of the formula

R^(1.1) denotes (a) F, CH₃, —OH, —O—CH₃ or CF₃, or a tautomer or saltthereof.
 6. A Compound of the formula I according to claim 1, wherein R¹denotes a group of the formula

or a tautomer or salt thereof.
 7. A compounds of the formula I accordingto claim 1, wherein R¹ and R² together with the nitrogen atom to whichthey are bound denote a group of from the formula

or a tautomer or salt thereof.
 8. A compound of the formula I accordingto claim 1, wherein R³ denotes a group of the formula IV

A independently of one another denote C—H, C—F or N, R^(3.1) denotes (a)H, halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N, C₁₋₃-alkyl-C(O)—NH,C₁₋₃-alkyl-S(O)₂—NH, —CN, —OH, —O—C(O)—NH—C₁₋₃-alkyl, C₁₋₄-alkyl,R^(3.1.1)—C₁₋₃-alkylene, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,C₁₋₃-alkyl-S, a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylenegroup is substituted by up to two fluorine atoms and each methyl groupis substituted by up to three fluorine atoms, —C(O)—R^(3.1.2),—S(O)₂—R^(3.1.3), R^(3.1.1) denotes (a) H, C₃₋₆-cycloalkyl,C₅₋₆-cycloalkenyl, (R^(3.1.1.1))₂N, a saturated, mono- or diunsaturated5- or 6-membered heterocyclic group which is substituted at a nitrogenatom by a group R^(3.1.1.1) and is substituted at a carbon atom by oneor two groups R^(3.1.1.2), or a heteroaryl group which is substituted ata carbon atom by a group R^(3.1.1.2), R^(3.1.1.1) independently of oneanother denote H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, heterocyclyl,aryl-C₀₋₃-alkylene or heteroaryl-C₀₋₃-alkylene, R^(3.1.1.2)independently of one another denote H, F, C₁₋₃-alkyl, —CN, —OH,—O—C₁₋₃-alkyl, —CO(O)R^(3.1.1.2.1), H₂N, (C₁₋₄-alkyl)-NH,(C₁₋₄-alkyl)₂N, phenyl or phenyl-CH₂, a C₁₋₃-alkyl or —O—C₁₋₃-alkylgroup wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, or R^(3.1.1.2.1) denotes H, C₁₋₆-alkyl, benzyl, R^(3.1.2) denotes—O—C₁₋₃-alkyl, —OH, —NR^(3.1.2.1)R^(3.1.2.2), R^(3.1.2.1) denotes H,C₁₋₃-alkyl, R^(3.1.2.2) denotes H, C₁₋₃-alkyl, R^(3.1.3) denotes—NR^(3.1.3.1)R^(3.1.3.2), R^(3.1.3.1) denotes H, C₁₋₃-alkyl, R^(3.1.3.2)denotes H, C₁₋₃-alkyl, R^(3.2) denotes (a) H, halogen, —NH₂,C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N, C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O)₂—NH,—CN, —OH, —O—C(O)—NH—C₁₋₃-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₁₋₃-alkyl-O, C₁₋₃-alkyl-S, a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms,—C(O)—R^(3.2.1), —S(O)₂—R^(3.2.2), R^(3.2.1) denotes —O—C₁₋₃-alkyl, —OH,—NR^(3.2.1.1)R^(3.2.1.2), R^(3.2.1.1) denotes H, C₁₋₃-alkyl, R^(3.2.1.2)denotes H, C₁₋₃-alkyl, R^(3.2.2) denotes —NR^(3.2.2.1)R^(3.2.2.2),R^(3.2.2.1) denotes H, C₁₋₃-alkyl, R^(3.2.2.2) denotes H, C₁₋₃-alkyl,R^(3.3) denotes (a) H, halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,C₁₋₃-alkyl-C(O)—NH, C₁₋₃-alkyl-S(O)₂—NH, —CN, —OH,—O—C(O)—NH—C₁₋₃-alkyl, C₁₋₄-alkyl C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₁₋₃-alkyl-O, C₁₋₃-alkyl-S, a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms,—C(O)—R^(3.3.1), —S(O)₂—R^(3.3.2), R^(3.3.1) denotes —O—C₁₋₃-alkyl, —OH,—NR^(3.3.1.1)R^(3.3.1.2), R^(3.3.1.1) denotes H, C₁₋₃-alkyl, R^(3.3.1.2)denotes H, C₁₋₃-alkyl, R^(3.3.2) denotes —O—C₁₋₃-alkyl,—NR^(3.3.2.1)R^(3.3.2.2), R^(3.3.2.1) denotes H, C₁₋₃-alkyl, R^(3.3.2.2)denotes H, C₁₋₃-alkyl, or R^(3.2) and R^(3.3) together with the carbonatoms to which they are attached form a monounsaturated 5-membered or amono- or diunsaturated 6-membered heterocyclic group or a 5- to6-membered heteroaryl group, wherein the heterocycles mentionedpreviously may contain a carbonyl, thiocarbonyl or cyanoimino groupadjacent to a nitrogen atom, and may optionally be additionallysubstituted at one or two nitrogen atoms by a group R^(3.3.3) in eachcase and may optionally be additionally substituted at one or two carbonatoms by one or two groups R^(3.3.4) in each case, R^(3.3.3)independently of one another denote C₁₋₄-alkyl or C₃₋₆-cycloalkyl,R^(3.3.4) independently of one another denote C₁₋₄-alkyl,C₃₋₆-cycloalkyl, halogen, CN, C₁₋₃-alkyl-O—, —NH₂, a C₁₋₃-alkyl orC₁₋₃-alkyl-O— group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or a tautomer or salt thereof.
 9. A compound of theformula I according to claim 1, wherein R³ denotes a group of theformula IV

A independently of one another denote C—H, C—F or N, R^(3.1) denotes (a)H, halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N, C₁₋₃-alkyl-C(O)—NH,—CN, —OH, —O—C(O)—NH—C₁₋₃-alkyl, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₁₋₃-alkyl-O, C₁₋₃-alkyl-S, a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(3.2)denotes (a) H, (b) halogen, —NH₂, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,C₁₋₃-alkyl-C(O)—NH, —CN, —OH, —O—C(O)—NH—C₁₋₃-alkyl, (c) C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O, C₁₋₃-alkyl-S, (d) a C₁₋₃-alkylor C₁₋₃-alkyl-O— group wherein each methylene group is substituted by upto two fluorine atoms and each methyl group is substituted by up tothree fluorine atoms, R^(3.3) denotes H, halogen, —NH₂, C₁₋₄-alkyl-NH,(C₁₋₄-alkyl)₂N, C₁₋₃-alkyl-C(O)—NH, —CN, —OH, —O—C(O)—NH—C₁₋₃-alkyl,C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O, C₁₋₃-alkyl-S, aC₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(3.2) and R^(3.3) togetherwith the carbon atoms to which they are attached form a monounsaturated5-membered or a mono- or diunsaturated 6-membered heterocyclic group ora 5- to 6-membered heteroaryl group, wherein the heterocycles mentionedpreviously may contain a carbonyl, thiocarbonyl or cyanoimino groupadjacent to a nitrogen atom, and may optionally be additionallysubstituted at one or two nitrogen atoms by a group R^(3.3.3) in eachcase and may optionally be additionally substituted at one or two carbonatoms by one or two groups R^(3.3.4) in each case, R^(3.3.3)independently of one another denote C₁₋₄-alkyl or C₃₋₆-cycloalkyl,R^(3.3.4) independently of one another denote C₁₋₄-alkyl,C₃₋₆-cycloalkyl, halogen, CN, C₁₋₃-alkyl-O—, —NH₂, a C₁₋₃-alkyl orC₁₋₃-alkyl-O— group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or a tautomers or salt thereof.
 10. A compounds of theformula I according to claim 1, wherein R³ denotes a group of theformula IVa

R^(3.1) denotes (a) H, F, Cl, Br, —NH₂, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂N,C₁₋₃-alkyl-C(O)—NH, —CN, —OH, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₁₋₃-alkyl-O, C₁₋₃-alkyl-S, a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(3.2)denotes (a) H, F, Cl, Br, H₂N, (C₁₋₄-alkyl)-NH, (C₁₋₄-alkyl)₂N,(C₁₋₃-alkyl)-C(O)—NH, —OH, C₁₋₄-alkyl, a C₁₋₃-alkyl or C₁₋₃-alkyl-O—group wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, R^(3.3) denotes (a) H, (b) F, Cl, Br, H₂N, (C₁₋₄-alkyl)-NH,(C₁₋₄-alkyl)₂N, (C₁₋₃-alkyl)-C(O)—NH, —OH, (c) C₁₋₄-alkyl, (d) aC₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(3.2) and R^(3.3) togetherwith the carbon atoms to which they are attached form a monounsaturated5-membered or a mono- or diunsaturated 6-membered heterocyclic group ora 5- to 6-membered heteroaryl group, wherein the heterocycles mentionedpreviously may contain a carbonyl, thiocarbonyl or cyanoimino groupadjacent to a nitrogen atom, and may optionally be additionallysubstituted at one or two nitrogen atoms by a group R^(3.3.3) in eachcase and may optionally be additionally substituted at one or two carbonatoms by one or two groups R^(3.3.4) in each case, R^(3.3.3)independently of one another denote C₁₋₄-alkyl or C₃₋₆-cycloalkyl,R^(3.3.4) independently of one another denote C₁₋₄-alkyl,C₃₋₆-cycloalkyl, halogen, CN, C₁₋₃-alkyl-O—, —NH₂, a C₁₋₃-alkyl orC₁₋₃-alkyl-O— group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, and R^(3.4) denotes H or F, or a tautomer or saltthereof.
 11. A compound of the formula I according to claim 1, whereinR³ denotes a group of the formula

or a tautomer or salt thereof.
 12. A compounds of the formula Iaccording to claim 1, wherein R³ denotes a group of the formula IVb

R^(3.1) denotes (a) H, F, Cl, Br, —NH₂, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂N,C₁₋₃-alkyl-C(O)—NH, —CN, —OH, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₁₋₃-alkyl-O, C₁₋₃-alkyl-S, a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(3.2) andR^(3.3) together with the carbon atoms to which they are bound form amonounsaturated 5-membered heterocyclic group or a mono- ordiunsaturated 6-membered heterocyclic group or a 5- to 6-memberedheteroaryl group, wherein the previously mentioned heterocycles containa carbonyl, thiocarbonyl or cyanimino group adjacent to a nitrogen atom,and may each optionally additionally be substituted at one or twonitrogen atoms by a group R^(3.3.3) and may each optionally additionallybe substituted at one or two carbon atoms by one or two groupsR^(3.3.4), R^(3.3.3) independently of one another denote C₁₋₄-alkyl orC₃₋₆-cycloalkyl, and R^(3.3.4) independently of one another denoteC₁₋₄-alkyl, C₃₋₆-cycloalkyl, halogen, —CN, —O—C₁₋₃-alkyl, —NH₂, aC₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or a tautomer or saltthereof.
 13. A compounds of the formula I according to claim 1, whereinR³ denotes a group of the formula IVb

R^(3.1) denotes (a) H, F, Cl, Br, —NH₂, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂N,C₁₋₃-alkyl-C(O)—NH, —CN, —OH, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₁₋₃-alkyl-O, C₁₋₃-alkyl-S, a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(3.2) andR^(3.3) together with the carbon atoms to which they are bound form amonounsaturated 5-membered heterocyclic group or a 5-membered heteroarylgroup, wherein the previously mentioned heterocycles contain a carbonyl,thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and mayeach optionally additionally be substituted at one or two nitrogen atomsby a group R^(3.3.3) and may each optionally additionally be substitutedat one or two carbon atoms by one or two groups R^(3.3.4), R^(3.3.3)independently of one another denote (a) C₁₋₄-alkyl or (b)C₃₋₆-cycloalkyl, and R^(3.3.4) independently of one another denote (a)C₁₋₄-alkyl, C₃₋₆-cycloalkyl, (b) halogen, —CN, —O—C₁₋₃-alkyl, —NH₂, (c)a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or a tautomer or saltthereof.
 14. A compounds of the formula I according to claim 1, whereinR³ denotes a group of the formula IVc

T denotes O, S, CH₂, NH or N—R^(3.3.3), R^(3.1) denotes (a) H, (b) F,Cl, Br, —NH₂, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂N, C₁₋₃-alkyl-C(O)—NH, —CN,—OH, (c) C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₃-alkyl-O,C₁₋₃-alkyl-S, (d) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, and R^(3.3.3)independently of one another denote (a) C₁₋₄-alkyl or (b)C₃₋₆-cycloalkyl, or a tautomer or salt thereof.
 15. A compounds of theformula I according to claim 1, wherein R³ denotes a group of theformula

or a tautomer or salt thereof.
 16. A compound of the formula I accordingto claim 1, wherein U—V—X denotes —N═(C—R⁵)—N═, —N═(C—R⁵)—(C—R⁶)═,—(CR⁴)═(C—R⁵)—N═, and R⁴ denotes (a) H, (b) a C₁₋₆-alkyl orC₁₋₃-alkyl-O— group which is substituted in each case by a groupR^(4.1), (c) R^(4.2)R^(4.3)N, R^(4.2)R^(4.3)N—C₁₋₃-alkylene, (d)halogen, —CN, —OH, —COOH, C₁₋₃-alkyl-O, C₁₋₃-alkyl-O—C₁₋₃-alkylene,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄-alkylene,C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene, (e) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(4.1) denotes H, OH or —O—CH₃, R^(4.2) denotes H or C₁₋₃-alkyl,R^(4.3) denotes H or C₁₋₃-alkyl, or R^(4.2) and R^(4.3) together withthe nitrogen atom to which they are bound denote a 3- to 6-memberedheterocyclic group, R⁵ denotes (a) H, (b) a C₁₋₆-alkyl or C₁₋₃-alkyl-O—group which is substituted by a group R^(5.1) in each case, (c)—NR^(5.2)R^(5.3), NR^(5.2)R^(5.3)—C₁₋₃-alkylene, (d) halogen, —CN, —OH,C₁₋₃-alkyl-O—C₁₋₃-alkylene, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₄-alkylene, C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene, (e)aryl-C₀₋₃-alkylen-O— group, (f) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(5.1) denotes H, OH or —O—CH₃, R^(5.2) denotes H or C₁₋₆-alkyl,R^(5.3) denotes H, C₁₋₆-alkyl or —SO₂—C₁₋₃-alkyl R⁶ denotes (a) H, (b) aC₁₋₆-alkyl or C₁₋₃-alkyl-O— group which is substituted in each case by agroup R^(6.1), (c) R^(6.2)R^(6.3)N, R^(6.2)R^(6.3)N—C₁₋₃-alkylene, (d)halogen, —CN, —OH, —COOH, C₁₋₃-alkyl-O, C₁₋₃-alkyl-O—C₁₋₃-alkylene,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₄-alkylene,C₁₋₃-alkyl-C(O)—O—C₁₋₃-alkylene, (e) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(6.1) denotes H, OH or —O—CH₃, R^(6.2) denotes H or C₁₋₃-alkyl,R^(6.3) denotes H or C₁₋₃-alkyl, or R^(6.2) and R^(6.3) together withthe nitrogen atom to which they are bound denote a 3- to 6-memberedheterocyclic group, or a tautomer or salt thereof.
 17. A compound of theformula I according to claim 1, wherein the ring

denotes a group of the formula

or a tautomer or salt thereof.
 18. A compounds of the formula Iaccording to claim 1, wherein R¹ denotes a group of the formula

R² denotes H, R₃ denotes a group of the formula

the ring

 denotes a group selected from

or a tautomeror salt thereof.
 19. A compound of the formula I accordingto claim 1, wherein R¹ and R² together with the nitrogen atom to whichthey are bound denote a group of the formula

R³ denotes a group of the formula

and the ring

 denotes a group selected from

or a tautomer or salt thereof.
 20. A compound according to claim 1selected from the group consisting of : No. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

or a tautomer or salt thereof.
 21. A physiologically acceptable salt ofa compound according to any one of claims 1 to
 20. 22. A pharmaceuticalcomposition comprising a compound according to any one of claims 1 to20, or a physiologically acceptable salt thereof and a carrier ordiluent.
 23. A method of treating headache, migrain headache or clusterheadache which method comprises administering to a host in need of suchtreatment a therapeutically effective amount of a compound according toany one of claims 1 to 20, or a physiologically acceptable salt thereof.